Discovery and characterization of vertebrate sialoglycan-binding proteins

Liran Adler; Sharon Yehuda; Ajit Varki; Vered Padler-Karavani

doi:10.1016/j.smim.2025.101978

. Author manuscript; available in PMC: 2026 Jul 14.

Published in final edited form as: Semin Immunol. 2025 Jul 18;79:101978. doi: 10.1016/j.smim.2025.101978

Discovery and characterization of vertebrate sialoglycan-binding proteins

Liran Adler ^a, Sharon Yehuda ^a, Ajit Varki ^b,^*, Vered Padler-Karavani ^a,^*

PMCID: PMC13358205 NIHMSID: NIHMS2188285 PMID: 40683091

Abstract

All known life forms feature a dense ensemble of cell surface and extracellular glycans. In vertebrates this includes a high density of sialic acids (Sias), a family of acidic sugars typically capping glycans of cell surface or secreted glycoproteins and glycolipids. Since Sia was found to be the receptor for the influenza virus, many other pathogens have since been shown to recognize specific host sialoglycans as targets for their hemagglutinins, adhesins and toxins, often with remarkable specificity and high affinity/avidity. Other pathogens have evolved diverse mechanisms to evade host immunity by ‘molecular mimicry’ of host sialoglycans. Sialic acids also act as “biological masks”, preventing access to underlying structures. Until the late 1970s, it was assumed that endogenous sialoglycan-binding proteins (SGBPs) did not exist in vertebrates. Several such vSGBPs have since been discovered, characterized by distinct sialoglycan specificities but generally low affinity. Markedly different rates of evolution and “Red Queen” effects likely explain this striking difference from the high specificity and affinity/avidity of numerous microbial SGBPs (mSGBPs). Nevertheless, these vSGBPs play important roles in normal development, physiology and disease conditions, with implications for human evolution. This review describes the discovery and characterization of vSGBPs. Most are previously known proteins, and their sialoglycan recognition had been discovered serendipitously. Thus, we may be seeing the ‘tip of an iceberg’ with many more such proteins to be discovered. We also emphasize recent studies showing that SGBP properties are markedly affected by competing endogenous Sialomes, such that in vitro studies may need to be re-visited, under conditions present in vivo.

Keywords: Sialic acids, Vertebrate lectins, Paired receptors, Accelerated evolution

1. Introduction

All living cells in nature feature a dense coating composed of sugar chains (glycans) secreted from cells or attached to proteins or lipids as cell surface glycoconjugates (e.g. glycoproteins, proteoglycans, glycophospholipid anchors, glycolipids, lipo-oligo/polysaccharides) [1, 2]. Glycosylation is a metabolic non-template driven process that relies on availability of the monosaccharides building blocks, their activation with nucleotides, and a collection of enzymes that work sequentially, each taking one activated-sugar unit at a time, to build up cell-surface secreted glycans and glycoconjugates [3–6]. Their enormous diversity arises from the wide collection of monosaccharide building blocks, a large variety in their composition, linkages, length, branching, carrier molecules (protein/lipid), linkage to carrier (e.g. N/O-linked proteins), and cell surface spatial organization. All of these features can be modulated based on the metabolic state of cells, tissues and the host organism [2, 3]. Glycans are highly flexible and their presentation mode, density heterogeneity, and/or interactions with other molecules, can all affect their recognition [7–9]. Furthermore, cell surface glycans float in their surrounding aqueous milieu and present multiple different conformations perhaps in the form of “clustered saccharide patches” [10], that lock into a more confined position upon interaction with other molecules (e.g. glycans, proteins) [11–13]. Despite high diversity and flexibility of glycans, glycan—protein interactions can be highly specific and of high affinity, for example with antibodies that, in some cases, can even distinguish between glycans with a single oxygen atom difference [7, 14]. Yet, glycan interactions with proteins more commonly come into play or become intensified with avidity. Such multivalent interactions mediate, modulate or fine-tune biological activities, rather than operating as On/Off switches that are more common with protein—protein interactions [11, 13]. Notably, glycan-binding proteins can themselves be glycosylated, and their glycosylation could affect their folding, stability, cell surface expression and functionality. Glycan-binding proteins (GBPs, other than anti-glycan antibodies) can be either soluble or membrane-bound, although in some cases the extracellular domains can be released with specific proteases [15–19]. Based on their structural and evolutionary relationships, are classified as lectins or as glycosaminoglycan-binding proteins [6]. Lectins can also be divided into different classes based on sequence homologies and evolutionary relationships [6]. This review is focused on GBPs of vertebrates, that particularly interact with monosaccharides commonly found at the outermost position of glycans, the sialic acids.

2. Diversity of sialic acids and Sialomes

Sialic acids (Sias) are carboxylated 9-carbon backbone monosaccharides, that emerged during the Cambrian expansion about 530 million years ago [20–23], and primarily found in animals of the Deuterostome lineage (i.e. vertebrates and “higher” invertebrates) and notably on some of their bacterial pathogens [10,24–26]. These alpha-keto acidic sugars have evolved from more ancient prokaryotic nonulosonic acids into a large family of >50 structurally diverse variations of Sias in nature (Fig. 1A–C), that commonly cap glycans and glycoconjugates (Fig. 1D) [20, 25]. Systematic cataloging of natural sialic acids and other nonulosonic acids (NulOs), and their representation using the Symbol Nomenclature for Glycans [27], can be found at the NCBI website [28]. Most Sias are derived from N-acetylneuraminic acid (Neu5Ac) through modification of one or more of its hydroxyl groups or at the C5 position. Neu5Ac and its 5-hydroxylated form N-glycolylneuraminic acid (Neu5Gc) are the two most abundant Sias in mammals. A hydroxyl group instead of the amide at C5 results in Kdn that is found primarily in bacteria and “lower vertebrates” but can be present in soluble form even in humans [10,29–31], though likely originating from dietary sources or microbiome-mediated metabolism [29, 32]. The most common hydroxyl group modification is O-acetylation at C4/7/8/9 positions, and less common are 8-O-methyl or -sulfo, and 9-O-lactyl groups [21, 33]. Sias are linked through their C2 position to underlying glycans commonly by an α2–3/6-linkage to galactose or N-acetylgalactosamine (Gal/GalNAc) or α2–8-linkage to another Sia (some bacterial pathogens express α2–9-linkage or alternating α2–8/9-linkages) (Fig. 1B) [21, 34]. The myriad of Sia-containing glycans (sialoglycans) on cell surface (or secreted) glycoproteins and glycolipids make up a highly heterogenous forest-like “Sialome”. The diversity of the Sialome stems from the Sia type and its modifications, Sia linkage to underlying glycans, structure and complexity of the underlying glycans, sialoglycan linkage to the carrier molecule (i.e. N/O-glycans on proteins), carrier type (e.g. protein/lipid), and the density, heterogeneity and spatial organization of sialoglycoconjugates on the cell surface (Fig. 1A–E) [10]. The Sialome characteristically differs between related species, but also within the same organism it varies between cell types, developmental stages, healthy/diseased conditions, and it is dynamically altered upon diverse environmental signals [35]. The high diversity of the Sialome could be driven in part by pathogens that exploit Sias as targets for recognition [3, 36, 37], as had been suggested for the loss of Neu5Gc in humans, and accumulation of its precursor Sia Neu5Ac (Fig. 1A) [20, 38, 39].

Fig. 1. — Diversity of sialic acids and the Sialome. A. The structural diversity of the core structures of the most common naturally occurring sialic acids (Sias; >50 known variants), highlighting chemical modifications that contribute to their functional heterogeneity, including Neu5Ac, Neu5Gc, and Kdn, along with common modifications at C4, C5, C7, C8, and C9 positions (Note: the stereochemistry depicted at C7 is not correct as the bond should be pointing down, however illustrated upword for clarity of details in the drawing) B. Typical glycosidic linkages of Sia to underlying sugars, including α2–3, α2–6 (to Gal/GalNAc), and α2–8 (to other Sias), with some bacteria displaying α2–9 or alternating α2–8/9 linkages. Less common linkages are also shown as smaller images – see text for more details. C. Examples for structural diversity of glycans underlying Sias. D. Sias typically cap N- and O-linked glycans on glycoproteins, and also cap glycosphingolipids, forming sialoglycoconjugates. E. The organization of sialoglycoconjugates on the cell surface (spatial organization) adds another level of Sias diversity. Overall, the Sialome is an array of cell surface and secreted sialoglycans, highly variable in structure, density, and spatial organization, shaped by the Sia type, linkage, carrier molecule, and environmental or developmental context. This vast and dynamic glycan landscape differs across species, tissues, and disease states, and is influenced by host–pathogen interactions, including evolutionary pressures such as the loss of Neu5Gc in humans (Created in BioRender).

3. Biological roles of sialic acids

Sialoglycans on the top of cell surface and secreted molecules are perfectly positioned to facilitate a wide range of biological processes [20, 40]. Initially it was thought that Sias mediate cellular interactions merely through their biophysical properties, envisioned to provide a negative charge and hydrophilicity to cell surfaces or to orchestrate interactions by physically masking or uncovering underlying glycans to alter cell fate and function [20, 40, 41]. But while numerous pathogens (beginning with the influenza virus in 1960) [42] have long been known to express proteins and toxins that specifically recognize sialylated glycoproteins or glycolipids, almost two decades elapsed before the discovery of vertebrate proteins that exploit Sia recognition to mediate endogenous cellular functions, in diverse biological contexts [20], consistent with their longstanding evolutionary persistence [43–45]. Sias were even found to be essential for early embryonic development [46]. Interestingly, Sia-binding proteins (lectins) were also discovered in organisms that do not express Sia (e.g. plants, arthropods and mollusks), possibly for protection against sialylated-pathogens [35, 47], or for interactions with the more ancient nonulosonic acids.

The diverse biological roles of sialoglycans range from structural/biophysical roles (e.g. charge repulsion, neuronal migration, glomerular filtration etc.) to serving as immune recognition and interaction mediators, particularly differentiating self versus non-self [40, 48, 49]. Indeed, sialoglycans on host cells are effectively Self-associated molecular patterns (SAMPs) [50]. This intrinsic recognition of self blocks potential immune attack of host cells, and appears to be also important for intra-species recognition (e.g. gamete or fetus) (Fig. 2). In contrast, many viruses, bacteria and protozoa exploit this Sia-coat to infect the host through extrinsic recognition of non-self, by using this sugar coat as their gateway through pathogen Sia-binding proteins (e.g. Influenza, Plasmodium, Cholera, Helicobacter, Mycoplasma, Rotavirus, Polyoma virus, Coronavirus, Pertussis, Tetanus etc.) (Fig. 2). In addition, some pathogenic bacteria and protozoa use Sia molecular mimicry to evade host immune responses, by coating themselves with sialoglycans similar to the host SAMPs protective-coat to mask immune binding-sites or antigens (e.g. E. Coli K1, Gonococcus, Meningococcus, Campylobacter, Trypanosoma, Group B Strep etc.) [48,51–53] (Fig. 2). These concepts of Sia-mediated self/non-self–immune recognition and responses were propagated by the discovery of several such vertebrate sialoglycan-binding proteins (vSGBPs) over the past ~50 years [24, 44]. Here we describe the (often serendipitous) discovery of some major vSGBPs, and highlight their physiological roles and evolutionary consequences on host homeostasis, disease conditions and host-pathogens interactions.

Fig. 2. — Multiple roles of sialoglycans in immune recognition and pathogen interactions. Sialoglycans act as self-associated molecular patterns (SAMPs), forming a protective glycan coat on host cells that can mediate self recognition by endogenous sialoglycan binding proteins (SGBPs) to prevent immune attack. In contrast, many pathogens exploit Sias, by binding to host sialoglycans for entry or by mimicking host SAMPs to evade immune detection. These opposing mechanisms highlight the central role of sialoglycans in distinguishing self from non-self during immune responses and host-pathogen interactions. Furthermore, secreted sialoglycoconjugates could also interact with Sia-binding proteins, as for example those made by fetal placenta to manipulate maternal immunity. Bacteriophages that evolve to target specific bacterial Sialomes add further complexity to these intreractions (Created in BioRender).

4. Historical view of the discovery of vertebrate sialoglycan-binding proteins (vSGBPs)

Table 1 summarizes the history of discovery of vSGBPs highlighting in chronological order their initial modes of discovery (often based on following up on serendipitous observations), sensitivity of the side chain to mild periodate oxidation and 9-O-acetylation, requirement for divalent cations, heparin-binding properties, and proposed biological functions of Sia recognition. Discovery methods ranged from early agglutination assays showing sensitivity to sialidase treatment or mild priodate oxidation and affinity chromatography to modern glycan arrays and structural studies. Functional relevance includes roles in immune regulation, fertilization, tissue growth, inflammation, and host-pathogen interactions.

Table 1.

Historical timelines and serendipity in the discovery of vertebrate sialoglycan binding proteins (vSGBPs)^#.

Protein(s)	Discovery of Sia Recognition	Mild Periodate	9-O-acetyl	Divalent Cations?	Heparin Binding	Some Known Functions of Sia recognition	Initial Discovery

Factor H	Sialidase Periodate	Loss of binding	Blocks binding	No	Yes	Discriminates self from non-self via recognition of host Sialomes, continually disrupting the alternative complement pathway	1978–1980 [73,110,111, 477]
Uterine agglutinin	Agglutination Affinity matrix	NS?	NS?	Yes	Yes	Paracrine effects on growth and development of the uterus, and modulating local immune responses during the reproductive cycle	1985 [56]
Selectins	Sialidase	No effect	No effect	Ca⁺² Mg⁺²	Yes	Interactions of platelets, leukocytes and endothelium, mediate leukocyte rolling and trafficking during inflammation and with cancer cells in metastasis	1985–1991 [242,249, 478–482]
L1CAM	Sialidase Cryo-electron tomography Glycan array	NS?	NS?	NS?	NS?	Neurodevelopment and disease	1991 [402]
Siglecs	Sialidase	Loss of binding	Can Block binding	No	No	Self Sialomes recognition, maintains tolerance, inhibiting immune responses, can be paired inhibitory/activating versions on the same cells.	1991–1993 [62, 63, 357]
Sperm egg-binding proteins	Competition assays, mass spectrometry	NS?	NS?	NS?	NS?	Fertility, mediate sperm recognition and binding to the egg’s zona pellucida	1995 [54, 55]
¹ BDNF	Endosialidase	NS?	NS?	No	Yes	Protect, localize and stabilize BDNF at neuronal surfaces	2000 [59]
² FGF-2	Endosialidase, Biochemistry	NS?	NS?	No	Yes	Modulating cell signaling, promoting cell growth, survival, and migration	2000 [57, 58]
PILRs	Sialidase	No Effect	NS?	No	No	Controlling leukocyte activation, regulating immune responses by inhibiting inflammation	2008 [69, 70]
³ CCL21	Chromatography	NS?	NS?	NS?	Yes	Enhancing immune cell (e.g. DC, T/B cells) trafficking and migration	2009 [74, 75]
M-Ficolin	Glycan Array	NS?	Facilitates binding?	Yes	No	Enhanced recognition of sialylated pathogen/ modulating immunity	2010 [68]
PECAM-1	Sialidase	NS?	NS?	No	No	Homophilic and heterophilic interaction in endothelial cells, regulates leukocyte migration and endothelial cell junction integrity	2014 [81]
HMGB1	Sialidase	No effect?	No effect?	Zn⁺²	No	Blocking HMGB1 binding to activating receptor, modulating inflammation and immune response signaling	2020 [72]
CD28	Array	NS?	NS?	No	No	Sialoglycans as alternate ligands for CD28 attenuate co-stimulation by CD80	2021 [71]

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NS indicates not studied, to the best of our knowledge.

Brain-derived neurotrophic factor (BDNF); fibroblast growth factor 2 (FGF-2); chemokine C—C motif ligand 21 (CCL21); high mobility group box 1 protein (HMGB1); sialic acid immunoglobulin-like lectins (Siglecs); paired Ig-like type 2 receptor (PILR), platelet endothelial cell adhesion molecule 1 (PECAM-1) cluster of differentiation 28 (CD28).

This table highlights some of the more established vSGBPs, as detailed in the main text. Few other limited studies described likely sialoglycan binding [20] with other previously known proteins, including Agrin [483], Laminin [484], CLEC-2 [483, 485, 486], and CD83 [487].

See Section 4.2.4. for Sia-binding by other neurotrophins and catecholamine neurotransmitters (e.g. NT-3, NT-4).

See Section 4.2.5. for Sia-binding by other growth factors (e.g. FGF-1, FGF-4, EGF, IGF-I, PDGF, TGFβ1).

See Section 4.2.6. for Sia-binding by other cytokine (e.g. IL-1, IL-4, IL-6, and IL-7) and Section 4.2.7. for Sia-binding chemokines (e.g. CCL3, CCL5, CCL27, CCL19).

Before being discovered as Sia-binding proteins, most of the currently known vSGBPs had been initially identified and investigated in the context of their other biological roles, with only subsequent discovery of their interaction with endogenous sialoglycans, then found to be important for their functions in health and disease [24]. It is now clear that sialoglycan-recognition by vSGBPs play key roles in vertebrate physiology, fertility, development and immunity. As such, sialoglycan–vSGBPs interactions had been shown to affect sperm—egg binding [54, 55], growth and development of the uterus [56] and stimulation of cell growth [57, 58]. vSGBPs also affect neuronal development and function, for example by localizing neurotrophins [59, 60] or by indirectly mediating uptake of neurotransmitters [61]. vSGBPs are critical for immune recognition of self-cells and of sialylated pathogens [45, 62–68], by which some interactions control leukocyte activation [69, 70], while others limit or rather activate innate or adaptive immune responses [45, 71, 72], or limit complement activation [73]. vSGBPs also mediate migration of immune cells [74, 75], as well as diverse interactions between platelets, leukocytes and endothelium [18,76–80], including homophilic and heterophilic interactions in endothelial cells [81].

vSGBPs are either soluble or membrane bound. Currently known soluble vSGBPs include Factor H, uterine agglutinin, brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF-2), chemokine C—C motif ligand 21 (CCL21), M-ficolin, and high mobility group box 1 protein (HMGB1), while membrane-bound vSGBPs include selectins, sperm—egg binding proteins, sialic acid immunoglobulin-like lectins (Siglecs), paired Ig-like type 2 receptor (PILR), platelet endothelial cell adhesion molecule 1 (PECAM-1), and cluster of differentiation 28 (CD28). Given that these vSGBPs play significant roles in the fine tuning of host physiology and immunity, and were much more difficult to find than microbial SGBPs, it is very likely that there are many more such vertebrate proteins that are yet to be discovered.

4.1. Defining sialoglycan-recognition by vSGBPs

Recognition of Sia by proteins can be determined by detection of Sias on the potential target molecule, competition over binding to potential target with free Sias or with sialoglycans, or by interfering with or inhibiting binding to targets by chemical or enzymatic cleavage of Sias from such target molecule.

The first methods developed for quantifying Sias in biological samples involved the chemical release of bound Sias from proteins and lipids followed by their reaction with a reagent that gives a chromophore measured by absorbance (e.g. resorcinol, thiobarbiturate; although resorcinol can be used without Sias release), however these colorimetric assays are of rather low sensitivity and specificity to Sias compared to modern methods, or destroy labile Sias modifications [33, 82]. Fluorometric methods are of higher sensitivity, in which Sias are released with mild acidic conditions that preserve different Sia species (e.g. Neu5Gc, Neu5Ac, O-acetylated Sias) [83] or by sialidase treatment, followed by derivatization with 1,2-phenylenediamines (e.g. 1,2-diamino-4, 5-methylenedioxybenzene dihydrochloride; DMB), which react selectively with alpha-keto sugars to form a sensitive quinoxaline fluorophore that can be resolved using reversed-phase HPLC and quantified against Sias standards [33, 84]. The specificity of DMB-HPLC is relatively high, though non-Sia alpha-keto acids could also be labeled. Sias could also be directly analyzed by liquid chromatography-mass spectrometry (LC-MS) at high specificity and sensitivity, but requires expertise and rather expensive equipment [84, 85]. Naturally, enzymatic methods offer the greatest specificity, particularly when using a sialidase (also called neuraminidase) to release Sias [30, 52, 82, 86] that can be quantified as described, or used for pretreatment of target in binding assays to inhibit Sia-specific interactions. To investigate Sias-interactions in their natural context, metabolic labeling within cells exploit glycan biosynthetic pathways to incorporate labels into sialoglycans (e.g. radioactive precursors [87], affinity tags, mass tags, structural modifications, and reactive handles), typically by using analogs of N-acetylmannosamine (ManNAc) that are converted into modified CMP-Neu5Ac [33, 88]. Of note, cell surface Sia can also be glycoengineered by supplementing the media with Sias that enter cells by macropinocytosis, delivered to lysosomes, exported into cytosol, then activated into CMP-Sia that become the donors for sialyltransferases [89], or possibly by a sialic acid transporter on the plasma membrane [90]. This method allows one to express certain Sia of interest to examine SGBP binding in the context of cells, as was done for recognition of Neu5Gc [91–93]. It should be noted that while this phenomenon can be quite robust in cultured cells, the in vivo situation is different because of rapid clearance through the kidney into the urine.

Sia recognition by glycan microarrays fabricated with a collection of sialoglycans is a robust tool used to examine protein recognition of a wide collection of sialoglycans, that include variations in their Sia modification, underlying glycan acceptors, carrier molecules and presentation modes [14,30,94–96]. It is worth mentioning that binding assays conditions must be controlled to avoid unintentional competition over binding to sialoglycans. For example, bovine serum albumin (BSA) that is commonly used as a blocking reagent in diverse binding assays, although not glycosylated on its own, contain contaminating Neu5Gc-rich bovine serum sialoglycoproteins, hence compete with binding to Neu5Gc-containing glycans [91,93,95,97,476].

Furthermore, Sia selective recognition by SGBP commonly rely on their interactions with the Sias C7–C9 polyhydroxy sidechain. Therefore, specific Sia-binding can be abolished after mild oxidation of this sidechain with sodium periodate (NaIO4). This treatment selectively truncates the sidechain, generating a reactive aldehyde at C7, that can be further reduced to a terminal hydroxyl with sodium borohydride, or for potential cross-linking into lysines at the binding site [98]. Of note, natural modifications on this Sias glycerol sidechain (e.g. O-acetylation) block periodate oxidation, limiting its use [33, 99], unless prior esterase treatment is done. Another characteristic feature of Sias is their negatively charged carboxylate at C1 position, which can be recognized by anion-binding domains within proteins (e.g. conserved arginine within Siglecs) [36, 88]. Alternatively, the binding could be mediated by cations within the protein binding pocket, especially by divalent calcium ions (Ca²⁺) [24, 88]. Of note, other anionic glycans could potentially compete with SGBP binding to this negative charge on Sias, particularly glycosaminoglycans (e.g. heparin) that are polyanionic owing to their carboxylated glucuronic acid and their sulfation modifications [24, 88].

Currently known vSGBPs have been shown to recognize sialoglycans using competition with free sialoglycans over binding to target sialylated molecules or cells, agglutination of red blood cells, affinity matrix, evaluate binding to target sialylated molecules or cells after pretreatment with sialidase to remove Sias completely (which is hard to achieve), or with mild periodate treatment to truncate the glycerol side chain of Sias [33, 82]. Later studies also used mass spectrometry to directly measure Sias, and glycan microarrays to examine binding against a wide collection of diverse sialoglycans.

4.2. Soluble vSGBPs

4.2.1. Factor H

The first soluble identified vSGBP is the major serum protein Factor H that functions as an important immune regulator of the alternative complement system. The complement system is an evolutionary conserved humoral innate immunity acting as a first line of defense, including in organisms that lack adaptive immune system. It is a network of > 50 proteins that function as effectors, receptors, and regulators that together tag particles and cells for clearance or killing [100]. They cooperate with innate and adaptive immune components, in circulation and on cell surface, to influence local and systemic immune functions that eventually mediate phagocytosis, cytolysis, and stimulation of T and B cells. Once these proteins recognize unique patterns on pathogenic, infected or damaged cells, a proteolytic cascade leads to elimination of various threats, supporting microbial defense, immune complex processing, and programmed cell death [100] (Fig. 3). The complement system is activated within seconds in an orchestrated proteolytic cascade by three pathways: classical, lectin, or alternative. Each of these pathways recognize differential patterns, but all merge and stimulate the formation of a C3 convertase (C4b2b or C3bBb), that is then propagated with various serine proteases to the formation of the membrane–attack complex (MAC; C5b-9), opsonin (C3b), as well as chemotactic and bactericidal peptide anaphylatoxins (C3a, C4a, C5a) [100] (Fig. 3). The classical complement pathway is activated by binding of the first complement component C1q to pathogen– or damage–associated molecular patterns (PAMPs or DAMPs; infected or damaged host cells, respectively), and by antigen–antibody complexes or pentraxins (e.g., c-reactive protein; CRP). The lectin complement pathway is activated upon binding of mannose-binding lectin (MBL), collectin, or ficolin to pathogen carbohydrates (e.g. mannose, glucose), and to IgM or IgA. In contrast, the alternative complement pathway is continuously active even on baseline low levels expression of C3b fragment, that can rapidly amplify on target particles becoming a strong opsonin for phagocytosis or mediate formation of MAC, supporting rapid reaction against foreign or abnormal cells [100] (Fig. 3). Indiscriminate deposition of C3b could potentially cause damage to host self-tissue, therefore host cells are protected by the soluble and highly abundant regulatory protein Factor H that limits the steady-state C3b tick-over activation within this alternative complement pathway [40,101–103] (Fig. 3).

Fig. 3. — Regulation of the alternative complement pathway by Factor H, a vertebrate sialoglycan binding protein (vSGBP). Factor H is the first identified vSGBP and a key regulator of the alternative complement pathway, a component of innate immunity that rapidly targets pathogens or damaged cells for destruction via opsonization, inflammation, and lysis. The system is activated through classical, lectin, or alternative pathways, all converging on C3 convertase formation and downstream immune effector generation. To prevent damage to host cells, Factor H binds C3b and host glycoconjugates to inhibit complement amplification. It has 20 complement control protein (CCP) domains, also called short consensus repeats (SCR), with distinct binding sites for C3b (CCP1–4 and CCP19–20), glycosaminoglycans (GAGs; CCP6–8 and CCP19–20), but only one binding site to Sia at CCP20. These are critical for distinguishing self from non-self, thereby orchestrating protection of host tissues from complement-mediated injury and cytolysis by membrane attack complex (MAC) (Created in BioRender).

Factor H (also called beta1H) is a 155 kDa sialoglycoprotein that plays a critical role in protecting host cells from potential self-damage by unrestrained activation of the host own complement [101, 103]. This abundant plasma glycoprotein (~500 μg/ml) operates in circulation and on the cell surface to distinguish self from non-self, in part through recognition of Sias as self-entities [40,103–107] (Fig. 3). The discovery of Factor H inter-connection with Sia was stimulated by classical methodologies used in 1960’s in the context of complement and Sias, mostly using killing and agglutination of red blood cells [108, 109]. Factor H was then studied for its role within the alternative complement pathway using erythrocytes of various species (e.g. mouse, rabbit, sheep, human), and it came as a surprise that some erythrocytes were susceptible while others were resistant to hemolysis, leading to the hypothesis that differing Sias content affect Factor H recognition and regulatory activity [73, 110, 111]. In 1978 it was shown for the first time that in hemolysis-resistant erythrocytes, alternative complement killing could be activated by (even partial) removal of Sias by a sialidase [110, 111], or by Sia truncation using periodate oxidation [110]. It was also established that the levels of hemolysis were inversely correlated with the degree of sialylation [73, 110], and that discrimination between activating and non-activating surfaces occurs after C3b deposition [73], upon direct interaction between Factor H and Sia [104]. These initial studies demonstrated that Factor H recognition of cell surface Sia facilitate its essential interaction with C3b to prevent effective activation of the alternative complement pathway. Follow up studies have shown that Factor H is blocked by Sia O-acetylation modification [112] and by calcium chelation [113], and it binds either Neu5Ac or Neu5Gc [114] favoring α2–3-linked Sia over α2–6/8-linked Sia [115] (Fig. 3). It had also been shown that local pH and sodium concentration could impact Factor H Sia binding [116]. Interestingly, Factor H own N-glycosylation carries Siaα2–6 thereby preventing intramolecular self-lock [114]. Importantly, while sialoglycans carry only few negative charges (one per Sia), cell surface sialoglycoproteins and sialoglycolipids can organize into polyanionic-rich “clustered saccharide patches” within the membrane (Fig. 2), supporting effective recognition of self-cells by Factor H.

Further studies with competing glycans suggested that Factor H also binds other negatively charged molecules as sulfated glycosaminoglycans (GAGs) that are ubiquitously expressed in human tissues [103, 104, 110, 111, 117, 118]. These polyanions are large linear polysaccharides with 40–100 repeating disaccharide units of an amino sugar and uronic acid (i.e. respectively N-acetylhexosamine, GlcNAc/GalNAc; and glucuronic/iduronic acid, GlcA/IdoA) attached to serine residues in proteoglycan core proteins. These include the proteoglycans heparin (HP), heparan sulfate (HS), chondroitin sulfate (CS), and dermatan sulfate (DS). Keratan sulfate (KS) is sulfated polyLacNAc, which can be found attached to N-glycans, O-GalNAc glycans, and O-Man glycans. As such, KS is not a typical GAG. Hyaluronic acid is a free polymer and not sulfated; as such, it is also not a typical GAG. Sulfated GAGs include CS/DS [4GlcAβ(IdoAα)1–3GalNAc–] and HP/HS [4GlcAβ(IdoAα) 1–4GlcNAcα1]. While HP is highly sulfated, HS is longer, less sulfated, and the most structurally diverse, playing key roles in cell differentiation, signaling, and immune homeostasis [119]. In addition to Sia, HS is the main polyanion mediating Factor H binding [103, 110, 111], while HP inhibit the classical complement pathway [120]. It had also been suggested that Factor H binds phospholipids thereby competing with C1q deposition in classical complement pathway [107, 121, 122].

Factor H robust binding to self-glycans protects host viable cells and tissues, while non-self structures are recognized by default as activating moieties. GAGs and Sia have been collectively referred to as polyanionic host self–associated molecular patterns (SAMPs) [50], however, it is now clear that their interactions with Factor H are not functionally redundant and rather specific, can dictate recruitment to selected tissues, and are mediated by unique functional domains within Factor H [103, 104, 107, 115, 123]. It has 20 short consensus repeats (SCR) also called complement control protein (CCP) domains that interact with C3b and cell surfaces. Factor H has multivalent binding sites to C3b at both N- and C-terminal domains at CCP1–4 and CCP19–20, and to GAGs at CCP6–8 and CCP19–20, but only one binding site to Sia at CCP20 (Fig. 3) [124–127]. Further structural studies revealed that Sia binding is mediated by evolutionarily conserved amino acids, including tryptophane (W1183) and arginine (R1215) [128]. Both GAG sites prefer HS over other GAG types, but differ in their relative affinities for de-sulfated forms of heparin [115, 117, 123]. Upon interaction with polyanions, Factor H self-associates into stable dimers and tetramers that support cluster formation on target cell surfaces for effective regulation of C3b [101, 107, 129]. Factor H domains also bind other ligands as pentraxins (e.g. CRP), nucleic acids of dying cells and extracellular matrix [102].

Many common pathogenic microbes, as well as cancer cells, evolve various strategies to disrupt complement attack [130–132], for example by covering their own surfaces with Sia to hijack Factor H protection [53, 103, 105, 132]. In contrast, defects in Factor H activity or its complete deficiency trigger complement-mediated chronic inflammation diseases that affect the eyes, kidneys and brain [102, 107, 133, 134]. Such tissue-specific injury is commonly mediated by autoantibodies, mutations or dysfunctional polymorphisms that perturb CCP19–20 domains of Factor H [118, 126, 133]. These host-glycans-binding-domains normally direct Factor H to selected tissues by interacting with unique sialoglycans and GAGs that function as tissue–’area code’, in which HS is dominant in endothelial cells and Bruch’s membrane in the eye, while sialylated glycans and other GAGs in kidney glomerulus [118, 129]. Eventually, malfunctioning Factor H leads to activation of alternative complement pathway and is highly associated with the diseases Atypical Hemolytic Uremic Syndrome (aHUS), Dense Deposit Disease (DDD) and Age-Related Macular Degeneration (AMD) [102, 107, 133, 134]. aHUS is a life-threatening extremely rare kidney disease characterized by formation of microthrombi in various small blood vessels, hemolytic anemia, low platelet count and impaired renal function, and is distinctly different from the more common typical HUS disorder, which is caused by foodborne gastrointestinal infection [133, 135, 136]. DDD, also termed membranoproliferative glomerulonephritis type II, is a rare renal disease primarily affecting children and young adults causing glomerular pathology that leads to end-stage renal failure in ~50 % of patients [133, 135]. AMD is a leading cause of central vision impairment in individuals >50 years of age [102, 106, 133, 134]. Clearly, Factor H has critical roles within host immunity, and identification of this first vSGBP triggered the discovery of additional vSGBPs that take part in Sia-mediated immune responses [137].

4.2.2. M-Ficolin

The lectin complement pathway is activated by mannose-binding lectin (MBL), collectin, or ficolin (Fig. 3), that share some structural features (Fig. 4) [138, 139]. Like Factor H of the alternative complement pathway, these lectins distinguish self from non-self by recognition of a vast number of carbohydrate ligands on microbial cell-surfaces, thereby supporting opsonization and complement killing of various pathogens [139, 140]. Three types of ficolins have been identified in humans: M-ficolin (ficolin-1; ficolin/P35-related protein), L-ficolin (ficolin-2; ficolin/P35), and H-ficolin (ficolin-3; Hakata Ag). In rodents, ficolin-A and ficolin-B are the orthologues of human L-ficolin and M-ficolin, respectively, while H-ficolin gene is a pseudogene [141]. H-ficolin and L-ficolin are both produced in the liver, while M-ficolin is uniquely produced by peripheral blood leukocytes and bone marrow cells, thus has a different expression profile [142, 143]. Ficolins are characterized by a C-terminal fibrinogen-like domain, that also contain the carbohydrate binding site, and an N-terminal collagen-like domain (fi-col-ins). While originally thought to bind TGF-β1 and elastin [144], all ficolins specifically recognize N-acetylglucosamine (GlcNAc) and other acetylated compounds (Fig. 4), but only M-ficolin (and its mouse counterpart ficolin-B) was shown to also recognize Sias, particularly 9-O-acetylated Sia [68, 140, 142, 145, 146], hence is identified as a vSGBP.

Despite ficolins’ structural similarity, it was more challenging to find the function and lectin properties of M-Ficolin [147]. It is circulating at low concentrations in the serum, but also found tethered to monocytes and granulocytes despite lacking a transmembrane domain [148]. In 2005 it was first identified as a secretory protein that activates the lectin complement pathway, with lectin binding to acetylated compounds, as GlcNAc and GalNAc, but also to sialyl-N-acetyllactosamine [142, 149], and the binding seemed to be calcium-dependent [142]. Later, advanced glycan array screening revealed that M-ficolin preferentially recognize 9-O-acetylated α2–6-linked sialylated glycans and various α2–3-linked sialylated glycans, including gangliosides (binding buffer contained 150 mM NaCl, 2 mM CaCl_2, 2 mM MgCl₂, thus potentially dependent on divalent cations as some other vSGBPs) [68]. Further structural studies showed that M-ficolin has an evolutionarily conserved N-acetyl-binding pocket, in which Tyr271 and Tyr283 residues play essential roles in the Sia binding specificity [68, 145], that is also pH-sensitive, affecting the ligand binding site that is dislocated at acidic pH [145]. Likewise, M-ficolin Y271F mutant is unable to bind Sia [150].

In the context of pathogen recognition, M-ficolin was shown to bind all examined sialylated encapsulated Group B Streptococcus of the Streptococcus agalactiae strains in a dose-dependent manner, in the presence of Ca²⁺. This binding was abolished by a sialidase pre-treatment of the bacteria, indicating Sia as the preferred ligand for M-ficolin on these bacteria [143, 146]. M-ficolin can also selectively bind other pathogens, and several single nucleotide polymorphisms (SNPs) have been shown to affect susceptibility to various infections [141].

M-ficolin Sia-binding was also shown to mediate self-recognition of leukocytes, allowing its tethering to the cell surface of monocytes and granulocytes [148, 151] at ~1 × 10⁵ M-ficolin molecules/cell [143]. This binding was dependent on divalent cations (Ca²⁺/Mg²⁺), and significantly decreased upon Ca²⁺ depletion by EDTA, and to a lesser extent with depletion with EGTA (EDTA is a generic chelator for many divalent cations, whereas EGTA is supposedly more specific to calcium ions) [148]. These findings also triggered investigation of M-ficolin interactions with the main membrane sialoprotein of human neutrophils, leukosialin CD43, revealing its role in neutrophils polarization, adhesion, aggregation, and complement activation [150]. In the context of pathophysiology, serum M-ficolin from pediatric cancer patients was strongly associated with neutrophil and monocyte counts in blood and bone marrow, suggesting that risk of chemotherapy-related infections could be related to serum M-ficolin [152]. Likewise, M-ficolin levels were higher in several inflammatory conditions, potentially serving as an inflammatory marker [140,152–157]. Such changes in serum levels of M-ficolin could potentially reflect changes in cell surface Sia on key immune cells, and further investigation is needed to better understand the role of this vSGBP in host inflammation and infection.

4.2.3. Uterine agglutinin(s)

As with complement studies, in late 1980’s many glycan binding proteins (GBPs, lectins) had been discovered by red blood cells agglutination or by affinity chromatography, specificity then deciphered by competition assays. Some lectins were inhibited by N-acetylglucosamine, but less inhibited by other non-charged monosaccharides, stimulating search for N-acetylneuraminic acid receptors [158]. In 1985, the first uterine agglutinin was identified from rats uterus by affinity chromatography (on fetuin-Sepharose column). Binding of this vSGBP was affected by pH, temperature, and Ca²⁺ (but not Mg²⁺ or Mn²⁺), inhibited by EDTA, and by sialoglycoproteins, Sia, sodium salt of glucuronic acid and heparin [56]. Heparin own binding to Ca²⁺, likely caused this agglutinin inhibition, similar to EDTA. Importantly, removal of surface Sia from erythrocytes by a sialidase abolished hemagglutination, supporting Sia-specificity [56]. Additional estrogen-induced Ca²⁺-dependent Sia-specific agglutinins were then discovered at different stages of rat uterine [159], and rat endometrium in its proestrus stage that showed specificity to Neu5Gcα2–6-linked sialoglycoproteins [160]. Likewise, human uterine agglutinin was discovered in endometrial scrapings taken at various stages of the menstrual cycle, revealing similar Ca²⁺-dependent binding, also recognizing sperm to which binding abolished after desialylation by a sialidase [161]. To the best of our knowledge, the rat/human uterine agglutinin have not been cloned thus far, so there is no clear evidence which specific protein is responsible for the observed agglutination activity in these species. In contrast, the uterine agglutinin in sheep and goats have been successfully cloned and identified as galectin-15 (LGALS15) [162–164], suggesting their differential carbohydrate recognition properties.

4.2.4. Neurotrophins

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/5 are structurally and functionally related proteins in the nervous systems. These homodimers selectively interact with the cell surface receptors p75NTR (low affinity) or tropomyosin-related kinase (high affinity; NGF to TrkA, BDNF and NT4/5 to TrkB, NT3 to TrkC>TrkA) to transduce intracellular signaling cascades, as MAPK pathway, PI3K pathway, and PLC pathway [165]. They play key roles in survival, development, and function of sympathetic and sensory neurons, in both the central and peripheral nervous systems, maintaining neuronal homeostasis and regeneration.

BDNF is widely expressed in the nervous system, gut, liver and other tissues, and is the most abundant neurotrophin in the brain, where it serves as a neurotransmitter modulator, supporting neurogenesis, neuronal survival and growth, and participates in neuronal plasticity that is essential for learning and memory [166–169]. Decreased levels of BDNF are associated with neurodegenerative diseases with neuronal loss, such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis and Huntington’s disease, as well as in depression, epilepsy, bipolar disorder and brain glioblastoma cancer [168,170–173].

BDNF operates in the CNS through its binding to p75NTR or TrkB, however it can also interact with other receptors in the brain, particularly the neural cell adhesion molecule (NCAM) [59]. NCAM and its glycosylated form with α2–8-linked polysialic acid (PSA) contribute to long-term potentiation in the hippocampus, thereby strengthening signal transduction in frequently-activated synapses to drive learning and memory. PSA is a polymerized structure of Sia with a degree of polymerization ranging from 8 to 400. It is expressed in embryonic brains, then mostly disappears leaving PSA-NCAM only in distinct regions of active neurogenesis in adult brain, as hippocampus and olfactory system. These antiadhesive polyanionic glycans play key roles in neural cell migration, axonal guidance, fasciculation, myelination, synapse formation, and functional plasticity of the nervous system [174]. Studies in NCAM-knockout mice suggested that PSA-NCAM interacts with BDNF to support long-term potentiation in the hippocampus [59]. Subsequently, in 2008, BDNF was identified as a soluble vSGBP that directly binds PSA, and requires α2–8-linked Neu5Ac polyanion of at least 12-mer, the minimum Sia units that can form a helix, and on average found as a 43-mer. BDNF and PSA form a large complex under physiologic conditions in terms of pH, NaCl, Ca²⁺ and Mg²⁺, that is inhibited at 10 times higher the concentration of these divalent cations [60]. The BDNF dimer is transferred to its receptors from this large complex, suggesting that PSA-NCAM important function is to present the BDNF to TrkB, thus concentrating this neurotrophin close to its site of action [60]. Similarly, polyanionic sulfated GAGs (HS, CS, and KS) had also been shown to form a large complex with BDNF, as well as with NT-3 and NGF. Furthermore, GAG-BDNF complex mediated binding to TrkB and p75NTR neurotrophin receptors [175]. Altogether, both PSA and GAGs play an important role displaying neurotrophins to their receptors within neuronal synapses [60, 175].

Other studies in 2011, used frontal affinity chromatography against PSA or PSA-NCAM to show that also the small molecules catecholamine neurotransmitters, norepinephrine, and epinephrine bind to PSA in its helical form that is important for this interaction [176]. Interestingly, dopamine binding to PSA-NCAM was completely lost, while BDNF binding reduced, when PSA was synthesized by a polymorphisms variant of the polysialyltransferase STX [STX(G421A)] that is found in schizophrenic patients. Furthermore, impairment of PSA by endosialidase modulated dopamine-induced Akt signaling, that is a characteristic feature in schizophrenia [176]. Thus, although Dopamine and other catecholamine neurotransmitters are small molecules that interact with sialoglycans, they may indirectly affect vSGBP interactions (e.g. BDNF).

In addition to PSA, sialylated glycosphingolipids (gangliosides) are also important in the brain, particularly the monosialylated GM1, which is the major ganglioside in the central nervous system. GM1 and other glycosphingolipids tend to cluster into lipid rafts within the cell surface membrane, together with various receptors and signaling molecules [177]. Immunoprecipitation studies have shown that GM1 interact with Trk receptors to enhance their NGF-induced signaling [178–180]. In addition, GM1 binds neurotransmitters within the neuronal synapse, supporting their presentation to high-affinity receptors [177]. Thus, GM1 activates neuronal differentiation and development by binding to soluble neurotransmitters, as well as to Trk and to other membrane proteins. However, GM1 also interacts with the divalent cation Ca²⁺ through its Sia moiety [177]. Given its importance, many neurological diseases are associated with impaired GM1 expression [177].

Clearly, important brain functions are mediated by neurotransmitters and neurotrophins, including neuronal signaling. Taken together, binding of these proteins to GM1 and to PSA, particularly in the context of PSA-NCAM, seems to be a critical feature for their normal functioning. Imbalance in GM1 and PSA amounts, quality or structural features could lead to serious consequences for neuronal functions, likely mediating various brain diseases as psychiatric disorders, such as schizophrenia, depression and bipolar disorder, as well as Alzheimer’s disease, Parkinson’s disease, and drug abuse [60,175–177].

4.2.5. Growth factors

Growth factors regulate embryogenesis and tissue regeneration, and are essential for stimulating cell growth, differentiation and survival. Some of these key proteins have been shown to be affected by Sia-containing glycolipids (gangliosides). Gangliosides are immune modulators affecting diverse cells, growth factors, chemokines and cytokines, also regulating cellular signal transduction by interacting with membrane proteins [181–184]. These sialoglycosphingolipids reside in the plasma membrane of eukaryotic cells, but can also be shed into the microenvironment, and circulate as free components in plasma or integrate back into cells [181, 185]. Exogenous gangliosides had been shown to affect the angiogenic activity of fibroblast growth factor-2 (FGF-2), which stimulated the discovery of the direct interaction between gangliosides and FGF-2, and other members of the FGF family [186].

FGF-2, also called basic FGF, is a cationic polypeptide that regulate diverse biological functions in the development and function of multiple organ systems, regulating cellular survival, proliferation, differentiation, migration, as well as angiogenesis and wound healing [187]. It interacts with the high-affinity tyrosine-kinase receptors (FGFRs) and with the low-affinity heparin and heparan sulfate proteoglycans on cell surfaces and in extracellular matrix [188, 189]. The heparin binding domain is enriched with positively charged amino acids as lysine and arginine [190]. In 1999, FGF-2 was shown to also directly interact with gangliosides, established by chromatography, binding to immobilized FGF-2, and successful competition with gangliosides, but not with free Sia [186]. Similarly, FGF-1 and FGF-4 were affected by gangliosides [186]. Free gangliosides interact with the positively charged FGF-2 C-terminal region, inhibiting its binding to FGFR (by GT1b, GD1b, GM1, GM2, but not GM3 and asialo-GM1), though without affecting heparan sulfate proteoglycans binding, suggesting different FGF-2 binding sites for gangliosides and for heparan sulfate. While free gangliosides inhibit the mitogenic activity of FGF-2 [186], membrane bound gangliosides promote this activity, in particular by FGF-2 binding to its GM1 required co-receptor [191]. Similarly, sulfated glycosaminoglycans differentially affect FGF-2 when examined as free versus cell-associated compounds [192]. Some studies suggest that Ca²⁺ interacts with the Neu5Ac anionic moiety of GM1 to activate neuronal differentiation and development [177], thus further investigation is needed to decipher the involvement of divalent cations in the context of gangliosides interaction with FGF-2.

Binding of FGFs to GAGs is affected by their degree of sulfation, positioning of sulfate groups, and molecular weight of heparin/heparan sulfate [57]. Studies into effects of other polyanions revealed that, in contrast to sulfated polysaccharides that were cytotoxic to cells, colominic acid (α2–8-linked polysialic acid; PSA) isolated from capsular Escherichia coli K1 slightly supported FGFs, while engineered sulfated-PSA strongly potentiated FGFs mitogenic activity, without any cytotoxicity, even at a high concentration and degree of sulfation [57]. Subsequently, it was shown that FGF-2 directly binds to PSA (of at least 17-mer), similar to its binding to neurotrophins (e.g. BDNF, NT-3, NGF) and catecholamine neurotransmitters (e.g. dopamine). This was achieved by electrophoresis, gel filtration, and surface plasmon resonance studies. In contrast to BDNF, FGF-2 binding to PSA was not affected by high salt nor by the divalent cations Ca²⁺ or Mg²⁺. FGF-2 binding to PSA-NCAM facilitated its oligomerization and binding to FGFRs, stimulating cell growth [58].

The vSGBP FGF-2 is the most studied growth factor in the context of their interactions with gangliosides and PSA. In humans, FGF is a family of 23 members, all of which are structurally related signaling molecules, hence systematic analysis of their interactions with sialoglycans is warranted. In addition to FGFs, recent evidence suggest that other growth factors could also be affected by gangliosides to support cell proliferation (e.g. EGF, IGF-I, and PDGF [193]) or by PSA (e.g. the transforming growth factor cytokine, TGFβ1 [194]) and the nature and role of their interactions with the Sia-moieties remains to be further investigated.

4.2.6. Cytokines

The cytokine superfamily is a network of soluble signaling proteins that coordinate between all cell systems and regulate the immune system. These are grouped into families based on structural homology of the proteins or their receptors, at large divided into cytokines and chemotactic cytokines (chemokines). The cytokines are further divided into interleukins, interferons, tumor necrosis factors, colony-stimulating factors and growth factors [195, 196]. These diffusible immune signaling proteins communicate and mediate diverse biological functions influencing growth, development, differentiation, survival, hematopoiesis, lymphocyte recruitment, T cell subset differentiation, inflammation and tissue repair [195, 196].

The interferons family of cytokines is expressed by a wide variety of cells in response to infection. They play a pivotal role in resistance to pathogens mediated by three main types of interferons (IFN-α, IFN-β and IFN-γ), each signaling through different receptors to transduce distinct, but overlapping, cellular effects [197]. In 1974 it was shown that plant lectins could inhibit interferon anti-viral activity, that could be restored by competition with fetuin [198], which is a highly sialylated protein with ~15–20 Sia per molecule, and ~1:1 ratio of (α2–3:α2–6)-linked Sia [199]. This was the first evidence for potential recognition of sialoglycans by interferons, and subsequent studies revealed that gangliosides are also recognized [200]. Furthermore, as part of their defense mechanisms, interferons modulate Sia expression on cell surface sialoglycoconjugates [201, 202]. With current understanding of the different types of interferons and their functions, it would be essential to investigate these potential vSGBPs with a fresh look to further explore their interactions with sialoglycans and how these may affect interferon functions.

The interleukins group of cytokines are expressed by leukocytes and many other cells. They elicit a wide variety of responses in cells and tissues with complex immunomodulatory functions, and play crucial roles in cells proliferation, activation, maturation, migration, adhesion and differentiation, particularly during inflammatory and immune responses [203]. Studies in the late 1990’s suggested that several interleukins (i.e. IL-1, IL-2 and IL-7) have lectin properties that could recognize selected glycans or glycoconjugates thereby influencing their functionality [204–207]. It was also clear that binding of two different cytokines to the same receptor could mediate differential signal transduction pathways, supporting the notion that interactions with cell surface glycans could potentially support such divergent responses. In 2001, further systematic assessment of diverse interleukins against a small selection of glycoconjugates revealed that IL-1, IL-4, IL-6, and IL-7 recognize selected sialoglycans in a calcium-independent manner. IL-1α binds Neu5Acα2–3-biantennary N-glycan, IL-1β binds GM4 ganglioside, IL-4 binds 1,7 intramolecular lactone of Neu5Ac, IL-6 binds glucuronic acid-3-sulfate containing glycans, and IL-7 binds sialyl-Tn antigen [208]. However, the methodologies involved indirect measurements on a limited set of crude compounds, thus warrants further investigation. Hence, there is limited evidence for sialoglycan recognition by the cytokine family members, simply because this had not yet been explored systematically with modern technologies.

4.2.7. Chemokines

Chemokines are a large family of >50 chemotactic cytokines, each containing a conserved motif of cysteine disulfide bonds, classified into four main subfamilies of C, CC, CXC and CX3C. They direct trafficking of cells in the body, best known for induction of leukocytes migration, and play fundamental roles in development, homeostasis, immune surveillance, inflammation, protection from infection, tissue repair, and regulating innate and adaptive immunity [209]. Chemokines interact both with cell surface chemokine receptors and with GAGs that function cooperatively to control cell migration [209, 210]. There are 25 chemokine receptors, each with seven helical transmembrane domains connected by hydrophilic loops, an acidic N-terminus chemokine-binding domain, and an intracellular C-terminus domain that mediate signaling by coupled G proteins. Tethering of chemokines to cell surface receptors on migrating cells transmit signals to promote cell movement, while their interactions with sulfated GAGs entrap chemokines on/near cell surfaces and extracellular matrix to set path for that cell movement [210, 211]. Chemokines fine-tune their functions through a wide range of their oligomerization designs and affinities for sulfated GAGs, that also play other roles in chemokine biology beyond localization and surface presentation [209–211].

Recognition of sialoglycans by several chemokines have been briefly explored in 2000’s, initially in the context of their interactions with the sialomucin P-selectin glycoprotein ligand-1 (PSGL-1). These studies showed that sialoglycans on PSGL-1 are not involved in CCL27 recognition (by N/O-glycan glycosidase and by sialidase) [212], while CCL21 and CCL19 recognition of sialyl-Lewis X glycan (core 2 O-glycan–branched SLeX) limited homing of T cells to secondary lymphoid organs [213]. Furthermore, glycopeptide microarrays revealed that CCL5, CCL19 and CCL21 strongly bind N-terminal region of PSGL-1 that contain tyrosine sulfation modification, however O-glycan branching and sialylation reduced CCL19 and CCL21 binding (confirmed by sialidase), without affecting CCL5, suggesting their differential regulation [214]. Thus, tyrosine sulfation, sialic acids, and branched O-glycans regulate CCL5, CCL19 and CCL21 binding to PSGL-1. O-glycosylation is also important for binding of CCL3 (MIP-1α) and CCL4 (MIP1-β) chemokines to their CCR5 chemokine receptor, which contains four sialylated O-glycans in its N-terminus and tyrosine sulfation [215]. Similarly, sialylation of CCR5 is required for CCL5 (RANTES) and CCL8 binding [216, 217]. Together, these finding suggest that glycosylation and sulfation of PSGL-1 and CCR5 is a dynamically regulated system, that could possibly be modified under different physiological and pathological conditions.

Given the importance of sulfated GAGs to chemokines functions, it was then postulated that the highly negatively charged PSA could also play a role. It was investigated in the context of dendritic cells (DC) migration, mediated by CCL21 and its chemokine receptor CCR7. In 2009, it was shown that TLR4-matured human DCs highly upregulate PSA expression that captures CCL21 to facilitate migration. Direct interactions between PSA and CCL21 was demonstrated by sialoglycan binding assays in the presence of high salt, Ca²⁺ and Mg²⁺, by sialidase, and by competition with Sia [74]. Similarly, it was shown that LPS-matured human and mouse DCs highly upregulate PSA by the polysialyltransferase ST8SiaIV, mostly on neuropilin-2 [75,218–220]. In mice, bone marrow-derived neutrophils and monocytes express PSA on NCAM (CD56) that is progressively down-regulated during migration to inflammatory sites, resulting in enhanced phagocytosis by matured macrophages [220]. Furthermore, PSA on matured DC enhance chemotaxis towards CCL21, but not CCL19, by PSA binding to its highly basic C-terminus domain [75]. Furthermore, sialylation of two N-glycosylation sites on CCR7 has inhibitory effects on CCL19 and CCL21 binding [221], while polysialylation is crucial for CCL21 recognition [222], and removal of cell surface PSA by a sialidase reduce CCL21-induced CCR7-mediated JNK and Akt signaling pathways [75]. Altogether, these data suggest that PSA expression is dynamically regulated during immune responses.

Sialic acids on CCR5 O-glycans and CCR7 polysialylation are critical for proper chemokine binding [75, 215, 222], and polysialylation of CCR7 controls its response to CCL21, but not CCL19. It had been suggested that sialylation on N/O-glycans and tyrosine sulfation in the N-termini of all CCRs is an emerging ‘multi-motif’ interactions pattern, that serves as a general regulatory mechanism [223], that together with GAGs underly the redundancy of the chemokine system and complexity of chemokine–receptor specific roles in facilitating immune responses [211, 223]. This type of regulation had also been reported for a wide range of other protein classes [223] warranting further in depth research.

4.2.8. HMGB1

High mobility group (HMG) proteins are a family of non-histone nuclear DNA-binding proteins with transcriptional regulatory properties, co-purified with histones and so called based on their relative high mobility on SDS-PAGE gels [224]. Within this family, high mobility group box 1 (HMGB1) is the most ubiquitous and evolutionarily conserved protein that is found in many eukaryotes (including vertebrates, tunicates, insects, and plants) [225]. HMGB1 is also a DAMP that drives a range of immune-inflammatory conditions, including sepsis, through its release from innate immune cells, mostly by macrophages and monocytes [72, 225, 226]. This nuclear protein can be passively released from cells undergoing necrosis and pyroptosis, or that bacterial endotoxins and various inflammatory stimuli induce post-translational acetylation, lactylation or phosphorylation of HMGB1 nuclear localization sequence enabling its translocation to cytoplasmic vesicles to be secreted extracellularly [225, 227]. During sterile tissue injury and during infection, levels of HMGB1 are elevated in serum and tissues, where it mediates its proinflammatory activity through binding to Toll-like receptors (TLRs) and RAGE on leukocytes and endothelial cells [72, 225].

In 2009, HGMB1 was shown to also mediate an anti-inflammatory response by binding to heavily sialylated CD24, that then selectively suppress the immune response to DAMPs through CD24 association with Siglec-10 in humans or Siglec-G in mice [228]. HGMB1–CD24 binding was found by co-immunoprecipitation followed by EDTA-disassociation, thus their binding is dependent on divalent cations [228]. Later it was shown that HGMB1 could similarly bind to heavily sialylated soluble CD52, that can then interact with Siglec-10 to trigger T cell suppression [229, 230]. Of note, binding buffer in these studies contained 150 mM NaCl, 3 mM MnCl₂, 1 mM CaCl₂, 1 mM MgCl₂, pH 7.6. This interaction was dependent on Sia, since sialidase treatment of CD52 abolished HMGB1 binding [230, 231]. Other studies further corroborated the Sia-binding lectin properties of HMGB1 using a sialoglycan microarray [72]. It was also proposed and validated in vitro that plasma sialoglycoproetins, estimated to contain ~2 mM Sia, serve as natural inhibitors of HMGB1 at physiological pH (pH 7.35–7.45) and zinc concentrations of ~100 μM. However, during sepsis, released lactic acid from anoxic tissues leads to acidosis (pH <7.3) and together with decreased zinc levels could disrupt Sia–HMGB1 interactions, releasing HMGB1 that then trigger the life-threatening inflammatory response [72]. Together, these studies established the dual role of HMGB1 vSGBP as a sensor of normal physiology or potent effector in inflammation or sepsis.

4.3. Membrane bound vSGBPs

There are four classical families of cell adhesion molecules (CAMs), including selectins, integrins, cadherins and immunoglobulin-like adhesion molecules. Most of these are typical transmembrane proteins that have extracellular, transmembrane and cytoplasmic signaling domains. In addition, adhesion G protein–coupled receptors (adhesion GPCRs) are hybrid molecules that share adhesive domains and functions with classical CAMs but are distinct in their G-protein-coupled signaling capability and cleavage-based regulation. They represent a bridge between adhesion and signal transduction, expanding the functional landscape of the CAM superfamily [232]. Another non-classical adhesion molecule is EpCAM that functions at the interface of adhesion, signaling, and proliferation, but does not belong to any of the classical CAM families (selectins, integrins, cadherins, or IgSF CAMs), nor to adhesion GPCRs. It forms its own class of signaling-capable adhesion molecules, with unique roles in development and cancer [233]. Historically, the serendipitous convergence of two parallel research paths, glycobiology and adhesion glycoproteins, led scientists to hypothesize that protein—glycan interactions are functionally important. This eventually led to discovery of many sialoglycan binding proteins that exert their actions through Sia recognition. Below we highlight several important vSGBPs families.

4.3.1. Selectins

Selectins are the first membrane-bound vSGBPs to be identified. Their discovery in the 1990’s was stimulated by convergence of the research into cell adhesion with that of carbohydrate biochemistry [234]. At that time, three cell surface glycoproteins were independently investigated on leukocytes, platelets, and endothelium in the context of their roles in leukocytes homing, platelet activation and adhesion, respectively (i.e. murine lymph node homing receptor or MEL-14 antigen, LECAM-l/LAM-1; granule membrane protein 140 or platelet activation-dependent granule external membrane protein, GMP-140/PADGEM; and endothelial-leukocyte adhesion molecule 1, ELAM-1) [234]. However, in spite of their selective expression and function, their cloning in 1989 [235–238] revealed that all originate from a cluster of homologous genes that encode similar proteins with a lectin domain [239], hence named selectins [238]. This had sparked intensive exploration of their carbohydrate ligands, greatly assisted by the fact that, at the same time, biochemists had already defined a wide variety of cell surface glycans in the context of lymphocytes adhesion and homing to lymph nodes [240, 241]. It was also shown that sialidase treatment of lymphoid tissues eliminated lymphocytes binding to high endothelial venules (HEV) in peripheral lymph nodes, thereby abrogating their homing capacity [242]. Shortly after in 1991, the prototype selectin-ligand was identified as a tetra-saccharide sialoglycan that contains a fucose termed – sialyl Lewis X [SLeX; Neu5Acα2–3 Galβl–4 (Fucα1–3)GlcNAc] [243–252]. Selectin–sialoglycans binding was then found to be Ca²⁺-dependent and reversible, inhibited by free sialoglycans, and diminished when leukocytes were treated with a sialidase [247].

The selectin family has three members named after the cell type in which they were first identified: L-selectin (CD62-L; leukocyte), P-selectin (CD62-P; platelet) and E-selectin (CD62-E; endothelial) [239, 253]. Both L-selectin and E-selectin had been discovered through their adhesion features, however, P-selectin was investigated as an adhesion molecule only after realizing its structural similarity with the other two selectins [234]. These Ca²⁺-dependent (C-type) lectins are type I single transmembrane N-glycosylated glycoproteins comprising an N-terminal carbohydrate-recognition domain, an epidermal growth factor (EGF)--like domain, a variable number of short consensus repeats (SCR; 60 amino acids each; as found in some complement proteins), a transmembrane region and a C-terminal intracellular cytoplasmic tail [17, 234, 254, 255] (Fig. 5A).

Fig. 5. — Structure, expression, and function of selectins and their glycan ligands in leukocyte trafficking and inflammation. A. The selectin family comprises three homologous type I transmembrane glycoproteins, L-selectin (CD62L), P-selectin (CD62P), and E-selectin (CD62E), each containing an N-terminal C-type lectin domain, an EGF-like domain, variable numbers of short consensus repeats (SCR), a transmembrane region, and a cytoplasmic tail. B. Selectins initiate the leukocyte adhesion cascade by binding to sialylated and fucosylated glycans (primarily SLeX), enabling leukocyte tethering and rolling on activated endothelium. This is followed by chemokine-mediated activation and integrin-dependent firm adhesion and transmigration. C. Selectins exhibit distinct but overlapping expression patterns and regulatory mechanisms: L-selectin is constitutively expressed on leukocytes and shed upon activation; E-selectin is induced on inflamed endothelium; P-selectin is stored in secretory granules of platelets and endothelial cells and rapidly mobilized upon stimulation. Furthermore, glycoprotein ligands such as PSGL-1, CD44/HCELL, CD34, and GlyCAM-1 present SLeX and its sulfated variants, mediating cell-type and context-specific interactions. PSGL-1 is a dimeric mucin-like protein and the dominant ligand for P-selectin and L-selectin. L and P-Selectins can also interact with sulfated glycans and glycosaminoglycans (GAGs) such as heparan sulfate (particularly for those with rare free amino groups; i.e. GlcN), which mimic dense glycan clusters. Dysregulated selectin-ligand interactions contribute to post perfusion injury, acute and chronic inflammation, thrombosis, and cancer metastasis, thus represent therapeutic targets (Created in BioRender).

These cell surface adhesion lectins mediate binding of leukocytes to endothelial cells to regulate their traffic and cell–cell interactions in immunity, homeostasis and inflammation [239, 253, 256]. Basically, selectins initiate the leukocytes adhesion cascade, allowing the tethering and slow rolling of leukocytes on blood vessel endothelium, that is then followed by chemokines-mediated cell activation (see Section 4.2. above) that lead to an integrin-mediated firmer cell–cell adhesion, and finally transmigration of the leukocytes through the endothelial cell layer into the underlying target tissue [239, 253, 256, 257] (Fig. 5B).

Although the selectins are closely related in structure and function, their cell expression patterns are different, and their activity is largely regulated by appearance/disappearance from the cell surface, and by conformational changes [234, 258–260] (Fig. 5C). At large, L-selectin is expressed on leukocytes, whereas E-selectin gene expression and prestored P-selectin expression is induced on activated endothelial cells and/or platelets [258]. L-selectin is constitutively expressed on the cell surface, and found on most circulating leukocytes, including lymphocytes, monocytes and neutrophils, but not expressed on endothelial cells [18, 258, 261]. Interestingly, in activated leukocytes there is a rapid and transient increase in L-selectin activity, but it is then rapidly shed through cleavage of its ectodomain by metalloproteases (e.g. ADAM-17) [15–18], as part of its regulation of leukocyte adhesion, migration and signaling [17, 18]. E-selectin expression is largely restricted to inflamed activated endothelial cells, where it is strongly upregulated by inflammatory cytokines, such as TNFα and IL-1β, that lead binding of NF-κB to regulatory domains in the E-selectin promoter [253,258,259,262–264]. Of note, human P-selectin promoter does not have an NF-κB binding site [254, 265]. Owing to this unique transcriptional regulation, E-selectin plays a crucial role in leukocyte capturing during chronic inflammation [253,258,259,262–264]. It was also found that in microvessels of skin and bone marrow E-selectin is constitutively expressed [266]. P-selectin is constitutively synthesized, but immediately stored intracellularly in α-granules of platelets and in Weibel–Palade bodies of endothelial cells. Within minutes of cellular activation by a proinflammatory stimuli (such as thrombin and histamine), it is rapidly mobilized from the membranes of these secretory granules to the surfaces of the activated platelets and endothelial cells. Recently, it was also found to be constitutively expressed on the surface of some vascular endothelia (e.g., in the lung and choroid plexus) [237, 256, 258, 262, 267, 268] (Fig. 5C).

Selectin ligands decorate various proteins and lipids on endothelial cells and leukocytes [17, 251, 254, 255, 269, 270]. All selectins bind selectively, but with low affinity, to the sialylated and fucosylated branched tetra-saccharide SLeX motif on glycolipids and on various N-glycans and O-glycans of glycoproteins [243, 255, 270]. Thus, SLeX is the minimal unit of a selectin ligand, on top or within a glycan chain [271], which is necessary but not sufficient to generate optimal binding by selectins [76, 271]. In human neutrophils, L-selectin is itself decorated with SLeX-containing N-glycans that serve as a ligand for E-selectin, mediating direct L-selectin–E-selectin interactions [272]. L-selectin also recognize sulfated variants of SLeX (6-O-sulfo-SLeX) [273] preferring this sulfo group at its underlying GlcNAc rather than at the Gal [274, 275], while E-/P-selectins are less sensitive to this modification [276]. 6-O-sulfo-SLeX are constitutively expressed on HEVs entering peripheral lymph nodes, and on other selected tissues, directing leukocytes into these areas [273,277–279]. L-selectin and P-selectin, but not E-selectin, also bind to particular sulfated glycans that lack Sia and fucose, such as proteoglycans [280–282]. However, selectins bind with higher affinity and avidity to several glycoproteins, most of which are mucin-like with repeating O-glycosylated peptide motifs [281] (Fig. 5C). Differential presentation of SLeX in the context of each glycoprotein mediate specialized adhesive functions during tethering and rolling [256, 271, 277].

P-selectin glycoprotein ligand-1 (PSGL-1; CD162) is the best characterized glycoprotein selectin ligand (see Section 4.2.7. above) that is constitutively expressed on all leukocytes and on activated endothelial cells [283–286]. PSGL-1 is a highly O-glycosylated mucin-like type I transmembrane protein, with sulfated tyrosines in its N-terminal region, and functionally operates as a disulfide-linked homodimer [257, 262, 284, 287]. It was originally identified by affinity isolation against P-selectin, but practically serve as a ligand for all selectins (P-/L-/E-selectin) [288] (Fig. 5C). It also binds chemokines when under-glycosylated, activates integrins and profoundly affects T-cell biology [287]. Antibody blocking and genetic deletion studies demonstrated that PSGL-1 is the dominant ligand for P-selectin and L-selectin on leukocytes, particularly on neutrophils and monocytes [287]. Genetic and synthetic glycosulfopeptides studies revealed that the optimal PSGL-1 binding motif has a short SLeX-containing O-glycan with several adjacent sulphated-tyrosines at the N-terminus of the protein backbone [262,289–292]. These sulfated tyrosine residues provide additional contacts, allowing selectins to bind with much higher affinity to PSGL-1 than to SLeX alone [262, 269]. Of note, both PSGL-1 and P-selectin are extended homodimers supporting stable rolling adhesions. It was shown that dimerization of selectins and their ligands stabilize cell rolling and enhance tether strength in shear flow [293–296].

P-selectin dimers on platelets and endothelial cells function as receptors for leukocytes where it mainly binds to dimeric PSGL-1 [297, 298]. However, it can also interact with CD24, particularly in the context of cancer [299]. E-selectin mainly binds to SLeX-containing glycans on PSGL-1, L-selectin (human not mouse), E-selectin ligand-1 (ESL-1; mouse not human), and the CD44 glycovariant hematopoietic cell E-/L-selectin ligand (HCELL) [255,300–303] (Fig. 5C). Each of these glycoproteins-ligands has distinct and dynamic contribution to selectin-mediated adhesion and signaling, as demonstrated for neutrophil [300, 304]. For example, E-selectin recognition of SLeX on L-selectin support transitioning of neutrophils from rolling to arrest [17]. In fact, L-selectin is a major regulator of leukocyte adhesion, migration and signaling [18]. While L-selectin interacts with E-selectin and PSGL-1, it prefers to bind endothelial cells surfaces (e.g. HEVs) through 6-O-sulfo-SLeX containing glycans on CD44 (HCELL), the mucin-like glycoproteins CD34, mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), and the secreted glycosylation-dependent cell adhesion molecule-1 (GlyCAM-1) [254,258,276,277,305–309] (Fig. 5C).

L-selectin and P-selectin can also recognize GAGs, such as HS [280–282,286,310–312], in a physiologically relevant manner [313–315]. It had been suggested that heavily glycosylated selectin ligands generate clustered saccharide patches that contribute to unique and stable interactions with selectins [24, 76, 316], and that GAGs mimic such patches with their dense carboxylic acid and sulphate ester groups [76]. Of note, dysregulation of selectins expression contribute to various inflammatory and thrombotic disorders [317–320], also supporting cancer progression and metastasis [77,321–323]. Interestingly, the highly sulphated GAG heparin could inhibit selectin interactions [311, 313, 324, 325], apparently independent of its anticoagulant effects [314], hence evaluated in the context of cancer therapy [326–328]. The selectin–ligand axis has been broadly explored in various inflammatory conditions and biomedical applications, beyond cancer [317]. Identifying changes in these adhesion molecules and their ligands is important for understanding variability in inflammatory responsiveness and disease susceptibility, and novel therapy approaches could specifically target leukocyte adhesion and migration.

4.3.2. Sperm—egg-binding protein

In 1980’s it was noted that binding of spermatozoa to eggs during fertilization is crucially dependent on appropriate recognition of surface carbohydrates, particularly in humans [329, 330], but also in Sea Urchins [331]. Subsequent studies in 1995 showed that interactions between human sperm and the egg zona pellucida (ZP) involve a selectin-like binding specificity [54]. These interactions were inhibited by the selectin inhibitor fucoidan (sulfated, fucose-rich marine polysaccharides) and SLeX, but not with fetuin that contains sialylated N-linked and O-linked glycans though lacking SLeX, nor with antibodies that inhibit selectins. Given that the mammalian zona pellucida glycoproteins are highly sulphated, it was suggested that the preferred ligand is sulfated-SLeX [54]. This was further corroborated by ultrasensitive mass spectrometry analyses that found SLeX to be the most abundant terminal sequence on the N-/O-glycans of human zona pellucida, and by inhibiting sperm–egg interactions by SLeX-containing glycoconjugates and by anti-SLeX antibodies [55, 332]. Using affinity chromatography followed by mass spectrometry analysis, chromosome 1 open reading frame 56 (C1orf56) was identified to be a SLeX-binding protein of capacitated spermatozoa [333, 334]. Furthermore, in assisted reproductive treatment, sperm quality could be significantly enhanced by selection against SLeX in the right context [335]. Nevertheless, full understanding of how exactly these interactions contribute to fertility is yet to be discovered, as well as the differentiation between the recognition of SLeX and sulfo-SLeX.

4.3.3. PECAM-1

CD31, a cell surface protein on platelets, leukocytes, and endothelial cells was investigated in midst 1980’s for its role as an endothelial cell junction molecule. Its cloning in 1990 revealed great similarity to the cell adhesion molecule (CAM) subgroup of the Ig superfamily, then renamed Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1; CD31) [336, 337]. This is a single pass transmembrane glycoprotein with a large extracellular domain and a shorter cytoplasmic tail. The extracellular domain has six immunoglobulin (Ig)-like C2-set domains, and the cytoplasmic tail contains immunoreceptor tyrosine-based inhibitory motif (ITIM) with several functional serine and tyrosine residues that are phosphorylated following cell activation and mediate signal transduction [337, 338]. This multi-functional protein is largely concentrated at junctions between adjacent cells, where it plays a major role in inflammation and vascular biology by regulating multiple stages of leukocyte transmigration through venular walls, stimulating endothelial cell motility, platelet function, angiogenesis and thrombosis, mechano-sensing of endothelial cell response to fluid shear stress and inhibiting apoptosis [339–341]. These diverse functions are mediated either by heterophilic interactions [342, 343] or by homophilic interactions [344].

At that time, it was known that most endothelial cell adhesion molecules are heavily glycosylated, and that endothelial glycans play roles in vascular physiology and pathology, particularly involving α2–6-linked sialoglycans [345, 346], which had prompted studies into Sia–PECAM-1 interactions. Investigating PECAM-1 in ST6Gal-I-deficient mice, Sia-binding/pull-down assays, sialoglycan competition studies and sialidase treatment, it was found that human PECAM-1 is a Sia-binding lectin, and that Siaα2–6-glycans regulate PECAM-1 homophilic interactions and downstream anti-apoptotic signaling [81, 347, 348] and angiogenesis in cancer [349, 350]. In fact, the sialoglycans mediate dynamic endothelial cell—cell interactions by stabilizing the PECAM-1 homophilic binding interface [351]. However, the mechanisms by which PECAM-1 interacts with itself may differ between species [352]. Overall, PECAM-1 is another critical vSGBP that have critical roles in immunity and further research is needed to decipher the particular Sia-type/linkage preferences in healthy physiology and in human disease conditions even beyond cancer.

4.3.4. Siglecs

Siglecs are the largest family of vSGBPs. Excellent reviews cover a historical perspective of their discovery [45,353–355]. Briefly, until the 1990s, Sia recognition was thought to depend mainly on its negative charge, and thus substituted by sulfate esters (i.e. Factor H, selectins). The discovery of Siglecs that specifically recognized Sia came from two key findings: sialidase-sensitive macrophage rosetting of red blood cells mediated by a novel protein called sialoadhesin [62, 356], and specific recognition of α2–6-linked sialoglycans mediated by an already well-known B cell molecule CD22 [357]. Further studies of recombinant soluble forms of CD22 confirmed and extended these findings. Shortly thereafter, cloning of sialoadhesin revealed it shared structure with CD22, as well as with CD33 and Myelin-Associated Glycoprotein (MAG) [358]. One group suggested the name of this family to be “ Sialoadhesins”. However, one of us suggested the term Siglecs (Sialic acid recognizing Ig-superfamily Lectins), and acceptance of the proposal was achieved by designating Siglec-1 as sialoadhesin, CD22 as Siglec-2, CD33 as Siglec-3, and MAG as Siglec-4.

Based on their immunoglobulin-like structure (I-type) and sugar-binding capabilities (lectin) Siglecs were classified as I-type lectins [36,45,359–361]. As more carbohydrate-binding IgSF proteins were discovered, a subgroup seemed to display structural and functional homology, while binding sialoglycans [62,356–358], then all the other Siglecs in humans and mice were discovered by sequence homology [353, 354]. The Siglecs can be broadly divided into two groups: the conserved Siglecs (such as Siglec-1, -2, -4, and -15), which are structurally and functionally preserved across mammalian species, and the CD33-related Siglecs (CD33rSiglecs) [45], a rapidly evolving subgroup (including Siglec-3, -5 through -11, -14, -16 and -17) that display high species-specific diversity and are much involved in fine-tuning immune responses to changing pathogenic and environmental pressures [45].

The Siglec family is the largest known subgroup of I-type lectins sharing significant amino acid sequence similarity and modular IgSF structure. Structurally, Siglecs are type I transmembrane proteins composed of an N-terminal V-set Ig-like domain responsible for binding sialylated glycans, followed by varying numbers of C2-set Ig-like domains, a transmembrane domain, and a cytoplasmic tail. Some Siglecs function as inhibitory receptors, carrying immunoreceptor tyrosine-based inhibitory motifs (ITIMs) or ITIM-like sequences that recruit phosphatases like SHP-1 and SHP-2 to dampen immune signaling (e.g., human Siglec-2, -3, -5, -6, -7, -8, -9, -10, and -11). Others act as activating receptors that contain immunoreceptor tyrosine-based activation motifs (ITAMs) associating with adaptor proteins such as DAP12 to promote immune activation (e.g., Siglec-14, -15, -16). Siglec-1 lacks a signaling domain and apparently does not directly participate in intracellular signal transduction [362], although it was reported to interact with DAP12 [363], and Siglec-4 was reported to interact with Fyn, a Src family tyrosine kinase [364], however these finding were not substantiated by others thus far. Two CD33rSiglecs are absent in humans, including Siglec-13 (deleted) and Siglec-17 (pseudogenized) [365].

Sia recognition by Siglecs is specific involving the Sia negative charge, but also depends on recognition of the Sia side chain (i.e C7, C8, and C9 carbons) and the identity of the 5-N-acyl group. Additionally, Siglecs are sensitive to Sia linkage (i.e. Siaα2–3, Siaα2–6, Siaα2–8), which contribute to their fine-tuned ligand specificity. Importantly, the N-terminal Ig-like V-set domain is responsible for Sia binding, with a conserved arginine residue playing a critical role in the recognition of the negatively charged carboxyl group of Sia. This conserved arginine is essential for ligand binding and is found in virtually all Siglecs, underscoring its functional importance [36]. These structural determinants enable Siglecs to recognize diverse sialoglycans on vertebrate glycoproteins and glycolipids, which allows them to distinguish between self and non-self glycans and modulate immune responses accordingly [36, 50]. Many Siglecs engage in cis interactions [366], binding Sia on the same cell surface, which can mask them and limit their ability to respond to external (trans) ligands [367]. However, Siglec-1 avoids cis masking due to its extended structure, allowing it to bind distant ligands [368, 369]. While cis interactions can dampen trans binding, they do not fully prevent it, as strong external ligands can outcompete cis ligands [369]. Some pathogens exploit this by expressing Sia, tricking Siglecs into treating them as self and suppressing immune responses [370]. Presumably as an evolutionary escape mechanism, Siglec-12 in humans has a fixed mutation of the arginine residue in its Sia-binding domain, which makes it unable to bind Sia [371]. The protein is therefore designated Roman numeral Siglec-XII, and is also undergoing negative selection for polymorphic pseudogenization to escape cancer risk [372].

Perhaps not surprisingly, some Siglecs also have non-canonical non-Sia ligands, to balance responses as Hsp70 [373] and/or another means to fight back rapid evolution of pathogens, e.g. Siglec-5 and Siglec-14 that recognize non-sialylated microbial proteins [374]. Siglecs are commonly expressed on immune cells, including B cells, T cells, dendritic cells, monocytes, macrophages, neutrophils, and NK cells, and play pivotal roles in the regulation of immune activation, tolerance, and inflammation [36, 366]. Excellent recent review papers described the diverse functional role of Siglecs in health and disease, including the role of Siglec—glycan interactions in regulating immune cells [362, 375], modulate macrophage phenotype and function [355], affect dendritic cell functions in tumor immunity [376], describe the role of inhibitory Siglecs [377], as well as Siglecs role in immune activation and tolerance [375], and the roles they play in viral infections and potential interventions [65], the impact of Siglecs on autoimmune diseases [64], Alzheimer’s disease[378], allergy and asthma [67], and cancer where Siglec receptors are described as new immune checkpoints [66] and as critical players within tumor immunity and immunotherapy [379]. Overall, Siglecs are important regulators of immune tolerance in autoimmunity and suppressors of anti-tumor immunity in cancer. As knowledge deepens, targeting the Sia–Siglec axis offers a powerful therapeutic avenue, both to dampen autoimmune responses and to boost cancer immunotherapy.

4.3.5. PILRs

Paired immunoglobulin-like type 2 receptors (PILRs) are a smaller family of I-type lectins composed of two functionally opposing members: PILRα, which is inhibitory and contains an ITIM motif, and PILRβ, which is activating and contains an ITAM motif [380, 381]. These receptors are expressed on multiple immune cells including natural killer (NK) cells, macrophages, and dendritic cells, where they modulate immune responses, especially T cell activity [381].

PILRs were initially identified based on their homology to other Ig-like receptors and their roles in immune regulation [380, 382, 383]. A key study in 2008 used X-ray crystallography to solve the structure of PILRα bound to its ligand, revealing that PILRα recognizes sialylated O-glycans, particularly those found on mucin-like glycoproteins, such as CD99 and neural cell adhesion molecule (NCAM) [70]. The critical residues responsible for Sia binding were found to form a specific groove that accommodates the Sia moiety, and mutational analyses confirmed the necessity of this pocket for ligand binding [69]. In fact, the ligand for both receptors is a CD99 protein, which is a sialylated O-glycosylated protein widely expressed on leukocytes and particularly abundant on activated T cells [70, 381]. Other sialylated ligands have also been described [384]. Binding of PILRs to CD99 is highly dependent on O-glycosylation, with specific glycosylation sites being critical for receptor engagement [69, 70, 384]. Interestingly, PILRα binds more strongly to CD99 than PILRβ, suggesting a dominance of inhibitory signaling within the paired receptor system – similar to other paired immune receptor families such as KIRs and CD94/NKG2 [381]. Structural studies, including crystallography and mutagenesis, have shown that Sia recognition by PILRs involves conserved residues [70], including a critical arginine residue found in both PILRs and Siglecs, hinting at evolutionary and functional similarities. Despite only ~22 % sequence homology with Siglec-1 (sialoadhesin) [69, 385], this shared arginine and Sia-binding capacity underscores a convergent function in glycan recognition. PILRs are still under investigation, but evidence suggests they contribute to immune homeostasis by selectively engaging sialylated ligands in a context- and glycosylation-dependent manner, with implications for inflammation, T cell regulation, and pathogen interactions [70]. Of note, some viruses exploit PILRα allowing their entry into immune-privileged sites, potentially dampening immune activation [386, 387]

4.3.6. L1CAM

Another Ig-superfamily member that has been reported to recognize Sia is the L1 family of cell adhesion molecules. These transmembrane glycoproteins are widely expressed in the nervous system and play critical roles in neuronal development and networking, including axon guidance, neurite outgrowth, neuronal migration, and synaptic plasticity [388–391]. L1 family members include L1CAM (L1), CHL1 (Close Homolog of L1), Neurofascin, and NrCAM (NgCAM-related CAM). These type I transmembrane glycosylated proteins are structurally-related and characterized by a conserved ectodomain composed of six Ig-like C2-set domains (as in Siglecs), followed by five fibronectin type III (FNIII) domains, a single pass transmembrane domain, and a short signaling intracellular tail that can activate tyrosine protein kinases and bind to cytoskeleton [388,390–393]. Defects in L1 family members are linked to numerous genetic neurological disorders, collectively referred as L1 Syndrome [95, 394, 395]. L1 is also overexpressed in various cancers supporting cancer growth and metastasis [396–399], hence investigated as a target for therapy and diagnostics [400, 401].

L1 family proteins not only mediate adhesion through homophilic and heterophilic protein—protein interactions, but also function as lectins for sialylated glycans, which is critical for their role in neurodevelopment and disease [390, 391]. Motivated by earlier studies on sialylated PSA-NCAM in the brain (see Section 4.2.4), in 1991 it was first shown that removal of PSA with a sialidase (endo-N) augmented L1CAM-mediated cell adhesion [402], suggesting that the adhesion was modulated by sialylation status. Subsequent functional studies revealed that L1CAM binds CD24 [403], specifically through its α2–3-linked sialoglycans, and that this interaction is critical for CD24-induced neurite outgrowth, also affecting cell aggregation patterns [389, 404]. Further key evidence for L1CAM Sia-recognition came from cryo-electron tomography [392, 393] and glycan array studies [95], which demonstrated that the L1CAM ectodomain binds sialylated glycans, and that this interaction is crucial for its homophilic adhesion properties, also confirmed by a sialidase treatment [392, 393]. Similar evidence indicates CHL1 binding to sialoglycans [95]. Interestingly, the Sia binding site contain a conserved arginine residue [389, 392, 404]. Although this Sia binding consensus sequences is similar to the arginine-motif within the Siglecs Ig V-set domain, the L1 family appears to distinctly feature this property in the fibronectin type III domain rather than in their Ig-domains [389, 392, 404]. Overall, L1 and CHL1 are confirmed vSGBP with mounting evidence that disrupted sialoglycan recognition contributes to their pathology. It is likely that other L1 family members (i.e. Neurofascin, NrCAM) may also engage in similar interactions with Sia owing to their structural similarities. Further understanding of these interactions may provide therapeutic targets for neurological disorders and cancer.

4.3.7. CD28

Cluster of Differentiation 28 (CD28) is a critical co-stimulatory receptor on T cells that binds CD80 and CD86 on antigen-presenting cells to promote full T cell activation, survival, and cytokine production. Structurally, CD28 is a homodimeric transmembrane glycoprotein belonging to the IgSF. Each monomer contains an extracellular V-set Ig-like domain, a transmembrane segment, and a cytoplasmic tail with signaling motifs, such as YMNM and PYAP, that activate downstream pathways including PI3K and NF-κB (different than ITIM/ITAM signaling) [405]. Recent findings revealed that CD28 can also bind sialylated glycans on both T cells and antigen presenting cells, a process that competes with its canonical interaction with CD80/CD86 and can suppress proper T cell receptor signaling and T cell activation [71]. This Sia binding was confirmed using glycan arrays and surface plasmon resonance, showing affinity comparable to Siglecs. Notably, when CD28 was pre-bound to CD80, its ability to bind sialoglycans was diminished, indicating competitive binding between Sia and CD80. Enzymatic removal of surface Sia restored CD28-mediated co-stimulation and enhanced T cell responses, including in exhausted T cells when combined with PD-1 blockade [71]. While many Sia-binding proteins use a conserved arginine for recognition [45], the specific residues involved in CD28 Sia recognition remain unidentified and merit further structural investigation. These findings uncover a previously unrecognized regulatory layer in T cell immunity, where sialylated glycans modulate CD28 function and immune responsiveness. Further studies are needed to confirm and extend these exciting findings.

5. Glycan binding specificity of vSGBP: dissecting the roles of sialic acids and heparan sulfates

Both Sia and heparin (and other GAGs) are negatively charged glycans that can compete for binding to certain host proteins, though their structural properties differ significantly. Factor H, a regulator of the complement system, binds heparin through CCP7 and CCP20, but engages Sia only via CCP20, suggesting overlapping yet distinct binding modes [124–127]. While early models emphasized electrostatic interactions, recent findings highlight specific structural recognition of Sia beyond charge. Selectins, which mediate leukocyte adhesion, also recognize sialylated ligands in a calcium-dependent manner; calcium stabilizes their carbohydrate recognition domain, while acidic pH enhances binding, particularly during inflammation [406, 407]. Heparin can inhibit selectin-mediated adhesion by mimicking sialylated ligands like SLeX [311, 313, 324, 325], or by structurally mimicking sulfated glycopeptide motifs [76], critical for P-selectin–PSGL-1 interactions [280–282,310,311] that rely on multiple sulfated tyrosine residues clustered at the N-terminus of PSGL-1 [262,289–292]. HMGB1, a nuclear alarmin released under stress, binds both heparin and Sia through arginine-rich motifs. Its glycan binding is pH-sensitive, favoring Sia at neutral pH and heparin in acidic environments [72]. These examples underscore that while negative charge facilitates initial attraction, specific glycan features, metal ions, and pH critically shape protein–glycan interactions.

6. Conserved arginine-mediated recognition of sialic acids by vSGBPs

Several soluble and membrane-bound vSGBPs use a conserved arginine residue to recognize Sia through electrostatic interactions with its negatively charged carboxyl group. This recognition is best exemplified by the Siglec family, where the conserved arginine is located in the V-set Ig-like domain [45]. This residue forms a salt bridge with the Sia carboxylate, and is essential for binding [36]. Interestingly, the sensitivity of Siglecs to mild periodate oxidation, which cleaves the Sia glycerol side chain, varies. Some Siglecs, such as Siglec-1, -2, -4, and -7 exhibit markedly reduced binding to Sia following mild periodate oxidation [408], highlighting their reliance on an intact glycerol side chain of Sia for recognition. In contrast, Siglec-9 and Siglec-11 maintain binding or exhibit altered specificity after periodate treatment [408], suggesting a more flexible mode of recognition, or potential dependence on modified forms of Sia. Notably, certain modifications to the Sia glycerol side chain, such as O-acetylation, can block periodate oxidation [33, 99], raising the possibility that Siglec-9 and Siglec-11 recognize such naturally modified Sias rather than being resistant to oxidation per se.

Factor H, a soluble complement regulator, also relies on a conserved arginine (e.g., R1215) within the complement control protein (CCP; SCR) domain 20 (CCP20), to engage Siaα2–3-linked glycans [128]. This binding is critical for distinguishing host cells from pathogens. PILRα, although not a Siglec, contains a Siglec-like fold and engages Sia via two conserved arginine residues within an Ig-like domain [70]. L1CAM, a neural adhesion molecule of the L1 family, recognizes Sia through a conserved arginine within its first fibronectin type III domain, which mimics the Siglec YXFR motif despite lacking a canonical Ig fold [389, 392, 404]. HMGB1, a nuclear protein that acts as an alarmin extracellularly, binds sialylated glycans through positively charged arginine-rich regions [72]. In contrast, other vSGBPs such as M-ficolin, selectins, PECAM-1, sperm—egg binding proteins, and CD28 do not use a conserved arginine for Sia recognition and rely instead on alternative binding sites and mechanisms, often in carbohydrate recognition domains (CRDs) or other structural motifs.

7. The Red Queen Effect: co-evolution of sialic acids and their binding partners in hosts and pathogens

Sia occupy a unique position in vertebrate biology, acting as critical terminal modifications on glycoproteins and glycolipids, particularly within the immune system [20, 40]. As markers of self, Sia help the host distinguish its own cells from pathogens [50]. However, this central immunological role has made Sia a prime target for microbial subversion, leading to an evolutionary arms race, an example of the Red Queen effect, where both host and pathogen must constantly evolve to maintain their relative fitness [1, 51]. This race is manifest at multiple molecular levels: in the diversification of host Sia structures, the evolution of vertebrate Sia-binding receptors such as Siglecs, selectins, and complement Factor H, and the adaptation of microbial Sia-binding proteins and mimicry strategies (Fig. 6). While microbial pathogens reproduce in minutes, many vertebrate hosts take years to do so, giving the pathogens much more opportunity to mutate.

Fig. 6. — Red Queen Effect dynamics of Sia–mediated host–pathogen co-evolution. The evolution of Sia diversity is somewhat constrained, by important roles of the Sialome in vertebrate development and physiology. Within these constraints, host organisms must evolve modifications to their Sialome to escape the pressure exerted by other Sia-exploiting pathogens and parasites. The figure illustrates the molecular arms race between vertebrate hosts and microbial pathogens driven by the immunological importance of Sia that cap glycans and serve as key markers of self and target of immune regulation. The central role of Sia in distinguishing host from pathogen has rendered it a hotspot of evolutionary conflict, a vivid example of the Red Queen Effect, where both host and pathogen must continuously adapt to maintain fitness. This evolutionary race unfolds across multiple molecular levels: [1] Pathogens evolve to utilize host Sia as receptors, enabling adhesion, invasion, and immune evasion. [2] Host Sia evolve to adjust to changes in Siglecs, adapting their structures through modifications such as O-acetylation or loss of Neu5Gc to preserve self-recognition while limiting microbial access. [3] Siglecs evolve to evade sialylated pathogens, refining ligand specificity or losing binding capacity to avoid being hijacked by pathogen-associated Sia. [4] Sia-expressing pathogens evolve to utilize Siglecs as receptors, co-opting host inhibitory pathways by mimicking Sia-containing self patterns (SAMPs). [5] Siglecs further evolve to adjust to changes in host Sia, evade Sia-mimicking pathogens, lose their canonical carbohydrate-binding domains, acquire mutations (e.g., in the conserved arginine), or form activating receptor pairs, reinforcing immune discrimination [6]. Host Sia continue to diversify to evade pathogens that exploit them as entry or recognition points, completing the co-evolutionary cycle. Notably, pathogen sialoglycan-binding proteins (pSGBP) evolve rapidly (e.g. bacteria reproduce at time scales of minutes), exhibit high specificity and high affinity, and are often easily detectable. In contrast, vertebrate Sia-binding proteins (vSGBP; e.g., Siglecs, selectins, Factor H) evolve more slowly (e.g. reproduce in time scales of years), under constraints of immune tolerance, with variable specificity, lower affinity, and are experimentally difficult to characterize. This asymmetry in evolutionary tempo and detectability further shapes the outcome of host–pathogen interactions. Together, these interlocking adaptations define a dynamic and molecular arms race where neither host nor pathogen may gain a permanent upper hand – each must keep evolving just to stay in place. However pathogens are more likely to win in the end. Of course, there are also selective pressures to change their Sialomes to avoid being specifically targeted and destroyed by viruses such as bacteriophages, which can replicate and evolve even faster. In yet another mechanism for selection, paired vSGBPs with identical binding properties mediate opposite effects (see Fig. 7). Based on Varki and Angata [36], modified for online viewing and publication [51], and further modified and expanded here (Using BioRender).

An example of this arms race occurred with the human-specific loss of the CMAH gene, which abolished the ability to convert Neu5Ac into Neu5Gc, thus eliminating Neu5Gc from the endogenous human glycome [23, 38]. This evolutionary event, dated to ~2–3 million years ago, apparently forced the human immune system to recalibrate its Sia recognition machinery. For example, Siglec-9, which in chimpanzees prefers Neu5Gc, evolved in humans to favor Neu5Ac, likely to maintain self recognition and avoid being hijacked by Neu5Gc-expressing pathogens [51, 409, 410]. This loss also created a dietary vulnerability: Neu5Gc can still be incorporated into human tissues from red meat, and its presence has been associated with inflammation, cancer, and increased susceptibility to certain pathogens [411–415]. Some bacterial sialidases, which previously favored Neu5Ac, have evolved altered specificity in response to Neu5Gc-rich diets [416–418], showing that microbial Sia-binding proteins evolve more rapidly and flexibly than their vertebrate counterparts.

This contrast in evolutionary tempo is striking. Vertebrate Sia-binding proteins, such as Siglecs, tend to evolve slowly, under constraints of immune tolerance and host integrity [45]. In contrast, microbial Sia-binding proteins, often used for adhesion or immune evasion, are under strong positive selection and exhibit high specificity and affinity, often targeting rare or modified Sia forms [419–424]. For example, the Salmonella typhi toxin PltB shows preferential binding to O-acetylated Neu5Ac, a modified form of Sia that alters its ligand properties [425, 426]. Similarly, some influenza viruses can evolve to recognize 9-O-acetylated Sia or 4-O-acetylated Sia as specific entry receptors, while such modifications can also inhibit viral sialidases, reducing infection efficiency [427–429]. This dual role, creating new ligands while masking others, demonstrates how Sia O-acetylation is itself a co-evolving immune shield, used by both host and pathogen.

Differences in speed of reproduction of microbes versus vertebrates affect the Siglec family host’s adaptive response. These receptors, many of which contain inhibitory ITIM domains, bind Sia as a means of detecting self and modulating immune activation. Pathogens such as Neisseria gonorrhoeae and Group B Streptococcus exploit this system by cloaking themselves in sialylated capsules or by recruiting host Factor H, the complement regulator that also relies on Sia for binding host surfaces [430–432]. The rapid evolution of Siglecs, through domain shuffling, gene duplication (e.g., paired receptors like Siglec-5/-14), and point mutations in the critical Sia-binding arginine, reflects a need to balance self-recognition with evasion of pathogen mimicry [45, 51, 365, 433]. Some Siglecs even evolve off the Sia-binding domain entirely, perhaps as a countermeasure to pathogen exploitation [45, 434].

Meanwhile, pathogens have not remained idle. In the oral and cardiovascular microbiomes, pathogens like Streptococcus oralis subsp. dentisani use proteins like AsaA (Associated with Sialic Acid adhesion A), a newly discovered adhesin with two Siglec-like domains [435, 436]. AsaA mediates binding to platelet’s Sia in infective endocarditis [435]. Remarkably, AsaA and similar proteins use a conserved arginine, akin to vertebrate Siglecs, to engage Sia, underscoring molecular mimicry at the domain level [435,437–442]. However, some bacterial Siglec-like proteins can bind Sia without the canonical arginine, implying the evolution of novel binding strategies whose mechanisms remain unknown [443]. This mirrors a broader trend in bacterial evolution: rapid adaptation via recombination, gene acquisition, and modular domain evolution.

The complement system also illustrates this evolutionary dynamic. Factor H, a negative regulator of the alternative complement pathway, binds preferentially to α2–3-linked Neu5Ac on host cells, distinguishing self from non-self [115]. Pathogens such as Neisseria meningitidis, Streptococcus pyogenes, and Yersinia enterocolitica evade complement attack by expressing Factor H-binding proteins (fHBPs) or mimicking host Sia [444–446]. The bacterium Borrelia burgdorferi, for instance, expresses multiple CRASPs (complement regulatory-acquiring surface proteins) that bind Factor H and FHL-1, conferring resistance to serum killing [447]. These interactions can be influenced by Sia modifications: O-acetylation of Sia inhibits Factor H binding, potentially tipping the balance toward complement activation [104, 112]. Such modifications are thus a double-edged sword: they protect against microbial sialidases or viral entry, but may also impair self-recognition by immune regulators.

Together, these examples support a dynamic model of co-evolution. (Fig. 6) Host Sias evolve structural diversity and modification (e.g., O-acetylation, loss of Neu5Gc) to fine-tune receptor interactions and resist microbial mimicry [448]. Siglecs evolve new recognition patterns, shed or duplicate domains, and recruit activating partners to counteract exploitation [45, 51, 449]. Microbial proteins evolve to bind host Sia with high affinity and specificity, co-opting immune pathways or hijacking complement regulators [445]. The Red Queen Effect governs this glycan-centered battle, where the survival of each side depends not on absolute advantage, but on keeping pace with the other’s innovations (Fig. 6).

In this race, glycobiology becomes immunology, and Sia become sentinels of evolutionary conflicts, constantly redefined by the pressures of microbial invasion and host defense. We may, in fact, be seeing only the tip of the iceberg: as glycomic technologies and structural analyses advance, new layers of this molecular arms race are likely to emerge, revealing deeper strategies of mimicry, evasion, and counter-adaptation at the interface of host and pathogen.

8. Paired receptors and sialic acids: balancing immune responses

A unique example for the evolutionary host—pathogen arms race is also exemplified in the concept of paired receptors, characterized by closely linked, highly similar genes in their Sia-binding domains that are subject to rapid evolution, driven by gene duplication and gene conversion shaped by selective pressure from pathogens, particularly in the context of Sia recognition [450–454]. Paired receptors are primarily found in two major gene families: the C-type lectin family and the IgSF [455]. These are structurally homologous immune receptors with opposing functions – typically one inhibitory and one activating – to help balance immune responses. This system allows for fine-tuned discrimination between self and non-self, or between homeostatic and inflammatory signals. Paired receptors usually retain high sequence homology in their extracellular domains, allowing them to recognize similar ligands, but key differences in their intracellular domains dictate their opposing functions [452, 455]. Inhibitory receptors typically feature a long cytoplasmic tail containing ITIMs, which recruit tyrosine phosphatases that downregulate immune signaling. In contrast, activating receptors generally have a short or truncated cytoplasmic tail and instead harbor a positively charged residue within the transmembrane domain. This charged residue facilitates interaction with adaptor proteins that initiate activation cascades, such as ITAM-bearing molecules like DAP12, CD3ζ, and FcRγ, or non-ITAM-containing adaptors like DAP10 [452, 455, 456].

In the Siglec family, Siglec-5 and Siglec-14 exemplify this paradigm: both bind sialylated glycans and share almost identical V-set domains, yet Siglec-5 contains a long cytoplasmic tail with ITIMs that mediate inhibitory signaling, while Siglec-14 lacks ITIMs and instead signals through the adaptor DAP12 to activate immune responses [373, 457, 458]. Similarly, Siglec-11 and Siglec-16 form another paired set with almost identical V-set sialoglycan binding domains: Siglec-11, expressed on microglia and tissue-resident macrophages, contains ITIMs and dampens inflammatory responses upon binding sialylated ligands, whereas Siglec-16 has a short cytoplasmic tail and signals via DAP12 to promote pro-inflammatory activation [433]. The PILRα/β pair follows the same logic – having very similar Sia-binding domains though PILRα is inhibitory with ITIMs, while PILRβ is activating and signals through DAP12 [383] (Fig. 7). These opposing functions, determined largely by the presence or absence of ITIMs and the length of the cytoplasmic tail, allow immune cells to finely tune their responses to pathogens, self-antigens, and tumor cells [383,459–462]. Therapeutically, targeting paired receptors offers a strategy to modulate immune tone – by blocking inhibitory Siglecs or PILRα to enhance immunity in cancer or infection, or activating them to suppress autoimmunity and inflammation.

Fig. 7. — Paired sialic acid-binding receptors balance immune responses through opposing signals. This schematic illustrates the paradigm of paired receptors, that are nearly identical binding domains, encoded by closely linked genes that perform opposing functions to maintain immune balance. Typically, inhibitory receptors such as Siglec-5, Siglec-11, and PILRα contain long cytoplasmic tails with immunoreceptor tyrosine-based inhibitory motifs (ITIM has one active tyrosine residue: I/V/L/SxYxxL/V), which recruit phosphatases (e.g., SHP-1 and SHP-2) to downregulate immune activation. Downstream of the ITIM, each of these receptors also carry immunoreceptor tyrosine-based switch (ITSM has one active tyrosine residue: TxYxxI/V), that can participate in SHP-1 and SHP-2 recruitment, though their exact contribution is less well characterized compared to the canonical ITIM. In contrast, their activating counterparts – Siglec-14, Siglec-16, and PILRβ – lack ITIMs but associate with immunoreceptor tyrosine-based activation motifs (ITAM)-bearing adaptors like DAP12 to trigger immune responses (ITAM has two active tyrosine residues: Yxx[L/I]x_6–12Yxx[L/I]). Upon phosphorylation, these tyrosines recruit SH2-domain-containing kinases such as Syk or ZAP-70, initiating activating immune signaling. Despite sharing very similar V-set extracellular domains and binding properties (due to ongoing gene conversion during meiosis; i.e. Siglec-5/14, Siglec-11/16, PILRα/β), their intracellular domains diverge, enabling possibilities for fine-tuned immune responses. However, this maybe the cause of relatively common polymorphisms that typically involve the elimination of the activating partner in the pair (Created in BioRender).

9. Navigating the competitive Sialome: in vitro versus in vivo realities

In the complex milieu of blood and extracellular fluids, sialic acid-binding proteins – including Siglecs, selectins, PILRs, PECAM-1, complement Factor H, and ficolins – must function amidst millimolar concentrations of competing endogenous sialoglycoconjugates and in the presence of heavily sialylated neighboring cells such as erythrocytes, platelets, and endothelial cells. Each of these proteins exhibits distinct preferences for Sia types and modifications leading to selective but overlapping recognition patterns that can result in competition for ligands. Importantly, Siglecs function within a constantly shifting landscape of Sialomes that vary over time, between tissues, and under different physiological or pathological states. These Sialomes represent a dense, multivalent, and low-affinity continuum of ligands, creating an analog (rather than binary) signaling environment, where the functional output of Siglec engagement reflects the integrated balance of cis and trans interactions with multiple ligand sources.

In vivo, this signaling is further influenced by physiological factors such as pH, sodium concentration, CO₂ buffering, and mechanical forces like shear stress, all of which are absent or distorted in simplified in vitro systems. For example, Siglec-9 on neutrophils binds to sialylated glycophorin A on erythrocytes, dampening neutrophil activation and oxidative burst responses [463]. This inhibitory mechanism is lost when neutrophils are studied in isolation, and dramatically altered in conditions such as sickle cell disease, where increased erythrocyte sialylation paradoxically results in reduced Siglec-9 binding due to changes in glycan presentation, contributing to elevated formation of neutrophil ROS (reactive oxygen species) and NETs (neutrophil extracellular traps) [464]. Another striking example is the behavior of the oral viridans group streptococci, which cause infective endocarditis. These bacteria express Siglec-like serine-rich repeat adhesins (e.g., GspB, Hsa, SrpA) that selectively bind sialylated platelet ligands in human whole blood, despite the overwhelming abundance of other sialylated glycoconjugates, highlighting how selective binding and virulence can only be properly understood in physiologically relevant settings [465].

Moreover, studies using whole blood anticoagulated with hirudin have shown markedly different outcomes compared to experiments in serum-containing media [72], further emphasizing how purification, artificial buffers, and media conditions can skew receptor-ligand interactions. The problem is compounded by the frequent contamination of commercial reagents, such as bovine serum albumin (BSA) and other protein preparations, with trace amounts of sialoglycoconjugates that can non-specifically bind Siglecs and other lectins, distorting experimental conclusions [91,93,97,476]. This is especially problematic in studies using glycan arrays, recombinant proteins, or simplified cell-free systems, which fail to replicate the complexity, multivalency, and dynamic competition of real biological environments.

Taken together, these insights strongly argue for a reevaluation of glycan-binding studies that rely solely on in vitro models. The physiological activity of Siglecs (particularly CD33rSiglecs) and other Sia-binding proteins cannot be meaningfully understood without accounting for the highly competitive, modification-sensitive, and context-dependent nature of Sia recognition in vivo. Furthermore, since human and mouse receptors often differ in expression and ligand specificity, humanized mouse models expressing human vSGBP (e.g. Siglecs) are essential for studying their functions in vivo [466]. Thus, rather than drawing conclusions from reductionist systems, future studies must embrace the complexity of native Sialomes and investigate glycan-protein interactions under conditions that preserve the full spectrum of biological variables.

10. Sialyoglycans as emerging immune checkpoints in health and disease

Sialoglycans act as immune checkpoint regulators by engaging inhibitory receptors like Siglecs, which modulate immune cell activity and help maintain self-tolerance [49, 467]. In cancer, tumor cells often overexpress sialylated glycans to suppress immune responses via Siglec-7, -9, or -10, making these pathways attractive targets for immunotherapy [66]. Beyond cancer, sialylation regulates innate immune responses in the central nervous system (CNS) [468–470] and influences interactions such as PSGL-1 binding to v-domain immunoglobulin suppressor of T cell activation (VISTA), where multiple post-translational modifications fine-tune immune signaling [214]. These examples highlight the multifaceted roles of sialoglycans in immune regulation and their potential as therapeutic targets.

11. The hidden landscape of vSGBP biological iceberg?

The discovery novel vSGBPs has often been serendipitous, starting with observations such as sialidase-sensitive hemagglutination or cell—cell interactions disrupted by sialidase treatment, suggesting the presence of sialic acid-specific lectins [24, 471]. Many membrane-bound vSGBPs were identified by isolating their extracellular domains or designing recombinant soluble forms, while soluble ones were typically purified via affinity chromatography using sialylated ligands [24]. More recently, discovery has been accelerated by bioinformatic predictions based on homology to known lectins [24]. New strategies to identify sialoglycan-binding proteins should focus on targeting the most promising biological contexts and applying advanced tools to detect relevant interactions. These could include bioinformatic approaches such as scanning protein databases for conserved binding motifs, especially the key arginine residue, combined with AlphaFold structural predictions [472] to identify candidate binding pockets. Experimentally, techniques such as affinity chromatography with sialoglycan ligands, mild periodate oxidation [33, 99] followed by crosslinking of adjacent proteins, screening against glycan microarrays [96], and metabolic labeling of cell surface glycans with azido sugars [33, 88] could enable the capture and characterization of glycan-binding proteins in more native, biologically relevant environments. However, the metabolic labeling approach may suffer uncertainty because it chemically modifies Sia that is the very structure being studied, which could alter natural binding interactions and potentially mask or misrepresent physiological recognition events.

New high-throughput and unbiased methods are now advancing the field. These include proximity-based chemical labeling using modified Sia to generate localized radicals that oxidize nearby proteins, capturing potential Sia interactors even if they lack transmembrane domains [88, 473]. Additionally, glycan—protein cross-linking mass spectrometry with enrichable linkers enables quantitative mapping of Sia–mediated interaction networks on the cell surface [474, 475]. These approaches, including nanometal surface energy transfer platforms, are helping uncover a broader array of Sia-interacting proteins, some involved in carbohydrate, ion, or protein binding, thus illuminating the diverse and previously underappreciated roles of sialylated environments in cell biology. These tools suggest that the vertebrate Sia-recognizing proteome is far more extensive than previously appreciated, likely only the tip of a much larger biological iceberg (Fig. 8).

Fig. 8. — Historical timelines of the discovery of vertebrate sialoglycan binding proteins (vSGBPs). A conceptual timeline illustrates the progressive discovery of vSGBP, from the first well-characterized proteins (e.g., selectins and Siglecs) to more recently identified or still-enigmatic members. Each milestone represents advances in understanding how Sia-binding governs key immune and physiological processes, from self-recognition and cell–cell communication to inflammation and disease. Despite the detailed characterization of some vSGBP, many remain incompletely understood, with unclear signaling pathways. The figure emphasizes that current knowledge is only the visible tip of a much larger iceberg: numerous vSGBP likely remain undiscovered due to technical limitations in traditional glycan-binding assays, which are often confounded by buffer artifacts, anticoagulants, and contaminant glycoproteins. These concepts highlight the urgent need for physiologically relevant models and outlines potential future discovery strategies, including affinity capture, chemical crosslinking, and AI-driven structure prediction, to reveal the full extent of this biologically critical protein family.

12. Perspectives and future directions

All vertebrate Sia-binding proteins discussed in this review have specific functions, yet defects in their activity can lead to major physiological consequences. Their importance stems from the critical role of Sia in human biology, especially within the immune system. Found on the outermost layer of nearly all cells, Sia are essential for distinguishing self from non-self, regulating immune responses, and facilitating cell–cell communication. These functions are fundamental to immune surveillance and cellular homeostasis. While some vSGBP are well-characterized, others, especially newly identified ones, still have unclear signaling pathways and mechanisms. Nevertheless, their strong association with serious diseases highlights the urgent need for continued research and the discovery of additional, yet-unknown proteins in this family. Importantly, in vitro glycan-binding studies with vSGBP often misrepresent their true biology due to artifacts from anticoagulants, buffer systems, and reagent contamination (e.g., BSA contaminated with sialylated plasma glycoproteins [91,93,97,476]). These simplified setups fail to capture the complexity and competition of glycan interactions in vivo, also showing dramatic differences when studied in whole blood. Thus, accurate insights into vSGBP require physiologically relevant models that reflect the native Sialome. Beyond that, a systematic search for more of these proteins is much needed, though the optimal methodologies for such a complicated task remains to be elucidated. While traditional techniques could still be used (e.g. affinity chromatography or mild periodate oxidation with cross-linking two adjacent proteins), current burst in artificial intelligence (AI) tools could also lead new directions within the search for additional vSGBP.

Acknowledgements

We thank the readers (Shani Leviatan Ben-Arye, Pascal Gagneux, Heinz Läubli, Takashi Angata) for helpful comments and the editors for their engagement. We apologize to all whose work could not be cited due to the depth and breadth of literature in this extensive field. This work was supported by Israel Scholarship Education Foundation (ISEF), Yoran institute for personalized medicine, and Yuri Milner global foundation (SY), by European Commission Horizon 2020 grant ERC-2020-COG-101003021 and by Israel Sciece Foundation - Israel Precision Medicine Partnership grant ISF-IPMP-3042/22 (V.P-K.), and by NIH grant R01GM03273 (A.V.).

Footnotes

CRediT authorship contribution statement

Liran Adler: Writing - Original Draft. Sharon Yehuda: Visualization, Writing - Review & Editing. Ajit Varki: Conceptualization, Methodology, Formal analysis, Investigation, Writing - Original Draft, Writing - Review & Editing, Funding acquisition. Vered Padler-Karavani: Conceptualization, Methodology, Formal analysis, Investigation, Writing - Original Draft, Writing - Review & Editing, Visualization, Supervision, Funding acquisition.

Data availability

No data was used for the research described in the article.

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Data Availability Statement

No data was used for the research described in the article.

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PERMALINK

Discovery and characterization of vertebrate sialoglycan-binding proteins

Liran Adler

Sharon Yehuda

Ajit Varki

Vered Padler-Karavani

Abstract

1. Introduction

2. Diversity of sialic acids and Sialomes

Fig. 1.

3. Biological roles of sialic acids

Fig. 2.

4. Historical view of the discovery of vertebrate sialoglycan-binding proteins (vSGBPs)

Table 1.

4.1. Defining sialoglycan-recognition by vSGBPs

4.2. Soluble vSGBPs

4.2.1. Factor H

Fig. 3.

4.2.2. M-Ficolin

Fig. 4.

4.2.3. Uterine agglutinin(s)

4.2.4. Neurotrophins

4.2.5. Growth factors

4.2.6. Cytokines

4.2.7. Chemokines

4.2.8. HMGB1

4.3. Membrane bound vSGBPs

4.3.1. Selectins

Fig. 5.

4.3.2. Sperm—egg-binding protein

4.3.3. PECAM-1

4.3.4. Siglecs

4.3.5. PILRs

4.3.6. L1CAM

4.3.7. CD28

5. Glycan binding specificity of vSGBP: dissecting the roles of sialic acids and heparan sulfates

6. Conserved arginine-mediated recognition of sialic acids by vSGBPs

7. The Red Queen Effect: co-evolution of sialic acids and their binding partners in hosts and pathogens

Fig. 6.

8. Paired receptors and sialic acids: balancing immune responses

Fig. 7.

9. Navigating the competitive Sialome: in vitro versus in vivo realities

10. Sialyoglycans as emerging immune checkpoints in health and disease

11. The hidden landscape of vSGBP biological iceberg?

Fig. 8.

12. Perspectives and future directions

Acknowledgements

Footnotes

Data availability

References

Associated Data

Data Availability Statement

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