Beyond neurotransmission: the roles of serotonylation in physiological and pathological processes

Jia-Ming Wang; Feng-Hao Zhang; Yi-Ru Chen; Dan-Ni Chen; Xiao Wang; Hai-Yun Xie; Jiang-Feng Li; Jin-Dan Luo; Li-Ping Xie

doi:10.1186/s11658-026-00909-9

. 2026 May 5;31:108. doi: 10.1186/s11658-026-00909-9

Beyond neurotransmission: the roles of serotonylation in physiological and pathological processes

Jia-Ming Wang ^1,^#, Feng-Hao Zhang ^1,^#, Yi-Ru Chen ^1,^#, Dan-Ni Chen ^2,^#, Xiao Wang ^1,^✉, Hai-Yun Xie ^3,^✉, Jiang-Feng Li ^1,^✉, Jin-Dan Luo ^1,^✉, Li-Ping Xie ¹

PMCID: PMC13360216 PMID: 42087096

Abstract

Serotonin, also known as 5-HT, is a classical neurotransmitter produced both in the nervous system and in non-nervous system. Its involvement in various fundamental physiological processes and pathogenic conditions is significant, as it binds to a diverse array of functionally distinct receptors. Apart from binding to 5-HT receptors and activating downstream signaling cascades, recent studies have revealed a novel posttranslational modification named serotonylation, where serotonin is re-taken up by serotonin transporter and is covalently attached to target proteins ranging from histone proteins to nonhistone proteins. Transglutaminases (TGMs), especially TGM2, catalyze serotonylation through the transfer of serotonin to the glutamine residues of target proteins. This review aims to investigate recent progresses in understanding the involvement of serotonylation in physiological and pathological processes. In addition, this review emphasizes how to target serotonylation as a therapeutic strategy for disease management.

Keywords: Serotonin, Transglutaminase, Serotonin transporter, Intracellular processes, Targeted therapy

Introduction

The posttranslational modifications of proteins are ubiquitous within cells [1]. Amino acid side residues are often modified with certain chemical groups in living systems [2]. Posttranslational modification regulates various cellular processes such as DNA repair [3], nuclear export [4], transcription [5], transportation [6], and condensate formation [7]. Apart from the most well-known phosphorylation, novel posttranslational modifications including acetylation [8], lactylation [9], and ubiquitination [10] have emerged. Although monoaminylation has been proposed for decades, its function and underlying mechanism under both physiological and pathological conditions have only been identified recently [11]. Among the three main types of monoaminylation identified thus far (serotonylation, dopaminylation, histaminylation), serotonylation is the best illuminated.

Serotonylation is achieved through the formation of a covalent linkage between serotonin and targeted proteins under catalysis by transglutaminases (TGMs) [12, 13]. Serotonin is a classical neurotransmitter synthesized utilizing essential tryptophan [14]. Most serotonin is produced in serotonergic neurons within the brain and enterochromaffin cells lining the gastrointestinal tract [15] (Fig. 1). Interestingly, approximately 90% of serotonin comes from the peripheral system despite its well-known roles in the central nervous system [16]. In most cases, serotonin is distributed intracellularly and tends to utilize platelets as reservoirs [17], highlighting the strict regulation of serotonin in organisms. Serotonin permeating in the microenvironment could bind to 5-HT receptors (5-HTRs) located in the plasma membrane [18, 19]. All 5-HT receptors, except for 5-HTR3, belong to the G-protein-coupled receptor superfamily (GPCRs) [20]. Mechanistically, serotonin binds to the Gα_i/Gα_q/11/Gα_s subunits of 5-HTRs and activates downstream signaling cascades such as mitogen-activated protein kinases, phospholipase C/protein kinase C, and phosphoinositide 3-kinase [21, 22] to regulate multiple physiological or pathological processes.

Fig. 1 — Distribution of serotonin throughout the human body. A The central nervous system harbors 10% of serotonin. Serotonin is synthesized via the catalysis of TPH-2 and functions as a neurotransmitter to regulate neuronal processes. B The peripheral system harbors 90% of serotonin. Serotonin is synthesized via catalysis by TPH-1 in enterochromaffin cells. Produced serotonin could be stored in platelets to avoid degradation. This figure was drawn using the platform of BioRender (https://app.biorender.com/)

In addition to directly binding to its receptor, serotonin could also be re-taken up by cells through the serotonin transporter (SERT) distributed in the plasma membrane [23]. Previously, it was believed that serotonin reuptake by cells could terminate its function [24]. However, serotonin was later shown to be involved in protein transamidation in situ, independent of its classical role as a receptor-mediated molecule [25]. In support of this idea, 5-HT immunoreactivity in the nuclei of embryos from some invertebrate species such as mollusks, sea urchins, and teleost fish increased in a serotonin dose-dependent manner. However, this phenomenon was terminated when TGMs activity was blocked pharmacologically [26]. These observations indicated that the role of serotonin in protein transamidation was evolutionally conserved [26]. The term “serotonylation” was not officially introduced until 2003 by Michael Bader’s group [27]. Different from its traditional function in signaling cascade amplification, the identification of serotonylation suggested that serotonin could also directly modify related proteins. In addition, serotonylation of targeted proteins could prolong the signaling until protein degradation, while the serotonin receptor-mediated pathway could only induce transient signaling activation [28]. To date, serotonylation has been observed in both nonhistone and histone proteins as well as in both nervous and peripheral systems. In general, nonhistone serotonylation influenced mainly protein localization and catalytic activity, whereas histone serotonylation affected mainly the chromatin accessibility and transcriptional activity [4, 29–31]. Strictly regulated serotonylation could participate in various physiological processes such as platelet activation, insulin release, and the circadian rhythm [27, 32, 33]. Overdue serotonylation was frequently seen in regions with high concentrations of serotonin, such as brain, gastrointestinal tract, prostate, and lungs [11, 34]. This could be attributed to elevated serotonin synthesis or uncontrolled serotonin secretion by platelets, neuroendocrine cells, or serotonergic neurons [11]. The resulting hyperactivation of related metabolic enzymes or increased chromatin accessibility could reshape the intracellular metabolic atlas or cellular structure, ultimately leading to pathological diseases or tumorigenesis [4, 35–37].

This review aims to summarize the present knowledge about how serotonylation is catalyzed, how serotonylation is detected, how serotonylation participates in both physiological and pathological processes, along with how to target serotonylation with greater specificity and greater effectiveness. We hope that our review will aid in “bench to bedside” translation to benefit more patients with abnormal serotonylation function.

Pathways concerning serotonin synthesis and degradation

The synthesis of serotonin was divided into two steps (Fig. 2). The first step started from the hydroxylation of tryptophan to 5-hydroxytryptophan, whereas the second step started from the conversion of 5-hydroxytryptophan to 5-HT [38].

The first step was the rate-limiting step and was catalyzed by the tryptophan hydroxylase (TPH) family [39]. The TPH family included TPH-1 and TPH-2 [40]. TPH-1 was expressed mainly in peripheral tissues and was responsible for the synthesis of serotonin in non-nervous tissues [41]. TPH-2 was expressed only in neurons and was responsible for the synthesis of serotonin in nervous tissues [42]. Moreover, the local synthesis of serotonin catalyzed by TPH-1 has been detected in pancreatic β-cells, lung cells, and adipocytes [43]. Owing to the presence of the blood–brain barrier, serotonin in peripheral tissues and nervous tissues were separated from each other and functioned independently [43].

The second step was executed by aromatic amino acid decarboxylase (AAAD) [44]. Newly synthesized 5-HT was packaged into granules or vesicles and transported to the cell surface. This process was facilitated by vesicular monoamine transporter family (VMAT) [45]. Released serotonin through exocytosis could interact with 5-HT receptors and activated downstream signaling pathways [46]. In addition, it could be re-taken up into cells by SERT to terminate the effects of serotonin [23]. SERT was distributed in both peripheral tissues and nervous tissues including platelets, the central nervous system, the pulmonary vasculature, and the gastrointestinal tract [47, 48].

The degradation of serotonin was executed by mitochondrial monoamine oxidase A (MAOA) [49]. MAOA was an enzyme that bound to the outer mitochondrial membrane, where it catalyzed the oxidative deamination of monoamines [49]. MAOA oxidated serotonin to 5-hydroxyindolacetic acid (5-HIAA) [50, 51]. MAOA was present in both the brain and liver. In the brain, MAOA was localized to the mitochondria of neuronal somata, dendrites, axons, and nerve terminals [52]. Particularly high enzymatic activity of MAOA has been observed in terminal regions involved in monoaminergic neurotransmission [53]. The involvement of MAOA in mediating serotonin turnover had the potential to affect serotonylation within neural cells. In the liver, MAOA played similar roles, whereas the storage of serotonin in platelets prevented its degradation in the liver [54]. 5-HIAA was often adopted as a marker of serotonin level in an organism because it could be detected in urine [55].

Serotonin receptors and biological functions of the serotonin/serotonin receptor signaling cascade

Before the identification of serotonylation, the roles of the serotonin signaling cascades through serotonin receptors were widely researched. The classification of 5-HT was primarily based on receptor subtypes, molecular mechanisms of action, and functional localization (Table 1) [20]. The complexity of the 5-HT system arose from its multilayered regulation by 14 receptor subtypes [20]. 5-HT receptors encompassed two major superfamilies: G protein-coupled receptors and ligand-gated ion channels [20]. GPCRs were responsible for receiving chemical signals from the extracellular microenvironment and triggering the appropriate signaling response inside the cell [56]. All GPCRs shared a common structural signature. They weaved back and forth across the cell membrane seven times, creating a characteristic “7-transmembrane” structure [56]. Crucially, binding sites for G-proteins (guanine nucleotide-binding proteins) were located on both the C-terminal tail and the third intracellular loop, which connected the fifth and sixth transmembrane helices [57].

Table 1.

Key 5-HT receptor subtypes and physiological functions

Receptor	Signaling subunit	Primary location	Physiological functions
5-HTR1A	Gi/o (↓cAMP)	Raphe nuclei, hippocampus	Anxiety reduction, neurogenesis
5-HTR1B/D	Gi/o (↓Ca²⁺)	Cerebral vasculature	Migraine relief (vasoconstriction)
5-HTR2A	Gq/11 (↑IP3/DAG)	Prefrontal cortex	Cortical plasticity, hallucination
5-HTR3	Ligand-gated ion channel	Area postrema, gut	Emesis reflex, pain sensitization
5-HTR4	Gs (↑cAMP)	Hippocampus, gut	Memory enhancement, gastrointestinal motility
5-HTR7	Gs (↑cAMP)	Hypothalamus, vasculature	Circadian rhythm, vasodilation α-granules

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Central nervous system regulation

Mood and emotional homeostasis

Serotonergic neurons originating in the raphe nuclei projected extensively to limbic structures, including the hippocampus and amygdala [58]. Postsynaptic 5-HT1A receptor (GPCR) activation in these regions reduced anxiety responses by 35% and increased newborn neuron survival by 15% via cAMP/protein kinase A (PKA) signaling [59]. Elevated 5-HT release also boosted prosocial behavior in mice by 40% [60]. However, acute 5-HT release in specific circuits could induce anxiety [60]. The dorsal raphe nucleus/bed nucleus of the stria terminalis pathway utilized 5-HT2C receptors (GPCRs) to inhibit reward-related neurons in the ventral tegmental area and lateral hypothalamus, thereby amplifying fear responses [61, 62]. This mechanism explained the initial anxiety exacerbation observed with selective serotonin reuptake inhibitors prior to therapeutic onset [63].

Cognition and memory formation

Prefrontal 5-HT1A receptors enhanced working memory precision by modulating glutamate release [64]. In contrast, hippocampal 5-HT4 receptors (GPCRs) promoted long-term potentiation through cAMP-dependent pathways, which improved spatial memory efficiency by 25% [64, 65]. In patients suffering from Alzheimer’s disease, cortical 5-HT6 receptor (GPCRs) upregulation correlated positively with cognitive decline [65]. Although antagonists such as intepirdine aimed to enhance cholinergic transmission, their clinical efficacy remained limited owing to complex 5-HT receptor crosstalk [59]. Functional magnetic resonance imaging studies demonstrated a robust correlation (r² = 0.62) between 5-HT levels and default mode network connectivity, underscoring serotonin’s integral role in sustaining cognitive networks [66].

Sleep–wake regulation

Dorsal raphe 5-HT neurons promoted wakefulness by suppressing rapid eye movement sleep via hypothalamic projections [67]. The 5-HT7 receptor (GPCRs) regulated circadian rhythms, with genetic polymorphisms linked to insomnia and shift-work disorders [65]. Tuberomammillary nucleus histaminylation cycles further fine-tuned circadian gene expression, demonstrating epigenetic integration with 5-HT signaling [65].

Peripheral system regulation

Gastrointestinal motility

Enterochromaffin cells in the gut synthesized approximately 90% of the body’s 5-HT [68]. Acting as a paracrine messenger, 5-HT activated 5-HT3/4 receptors (5-HTR3: ligand-gated ion channel) on enteric and intrinsic primary afferent neurons to stimulate peristalsis and secretion [65], thereby coordinating the migrating motor complex essential for digestive efficiency. Dysregulation of 5-HT signaling contributed to pathologies such as irritable bowel syndrome, where mucosal 5-HT surges induced visceral hypersensitivity [69].

Hemostasis and vascular tone

Platelet-absorbed 5-HT promoted aggregation and vasoconstriction at injury sites via 5-HT2A receptors (GPCRs) [70]. Circulating 5-HT balanced vascular tone through 5-HT1B-mediated vasoconstriction and 5-HT7-induced vasodilation [71, 72]. Following subarachnoid hemorrhage, 5-HT1B activation exacerbated ischemia by potentiating 20-hydroxyeicosatetraenoic acid synthesis [71].

Metabolic homeostasis

Pancreatic β-cells were able to co-release insulin and 5-HT, which modulated insulin secretion in an autocrine manner through vesicular monoaminylation [73]. Hepatic 5-HT2B receptors regulated gluconeogenesis, while adipose 5-HT influenced lipid storage (5-HTR2B: GPCRs) [74, 75]. Paradoxically, 5-HT2 receptor activation induced insulin resistance via insulin receptor substrate 1 phosphorylation [76], whereas 5-HT4 agonism enhanced insulin sensitivity, indicating a duality complicating diabetes management [77].

Serotonin signaling through serotonin transporter

SERT modulated serotonin availability in the extracellular microenvironment through Na⁺/Cl⁻-dependent reuptake [78]. As a member of the solute carrier 6 (SLC6) family, SERT shared structural homology with transporters for dopamine, norepinephrine, creatine, proline, and γ-aminobutyric acid [79]. The 630-amino acid protein comprised 12 transmembrane helices with intracellular N- and C-terminal tails regulating uptake kinetics, trafficking, and protein–protein interactions [80, 81]. The C-terminus bound cytoskeletal and signaling partners including actin, vimentin, small GTPases, vesicular transport factors, and protein kinase C-anchoring proteins [82, 83], whereas the N-terminus interacted with secretory carrier membrane proteins and syntaxin [78, 82, 84, 85].

Active serotonin transport proceeded via an alternating-access mechanism driven by established electrochemical gradients or direct ATP hydrolysis [47]. Mechanistically, the transport of serotonin experienced the following three states: “outward-open,” “occluded,” and “inward-open” states [47]. Initially, the binding site of SERT faced the extracellular space [48]. One Na⁺ and one Cl⁻ binding induced a conformational shift that primed the transporter for serotonin recognition [86]. Serotonin in the extracellular fluid then bound to the complementary site on SERT. Once serotonin and all ions were bound, SERT underwent a major conformational change to become occluded [86]. This change blocked extracellular entry and temporarily “locked” serotonin, Na⁺, and Cl⁻ inside the protein [48, 86]. The transporter then reoriented toward the cytoplasm [87]. Owing to differences in ion concentrations between intracellular and extracellular environment, SERT’s affinity for serotonin and the ions sharply decreased [87]. As a result, serotonin, Na⁺ and Cl⁻ were released into the cytoplasm, either sequentially or simultaneously [87, 88]. Then, SERT returned to the outward-open state and proceeded with another round of transport, which was typically driven by K⁺ [79, 80, 89].

Discovery of serotonylation

Originally, SERT-mediated serotonin reuptake was viewed solely as a termination signal for serotonergic transmission [47]. However, intracellular function regarding serotonin was unknown, similar to many other amines. In the late 1950s, Heinrich Waelsch’s group described a new phenomenon in which mono or poly-amines could be incorporated into targeted proteins, which were catalyzed by TGMs in a Ca²⁺-dependent way [25]. They termed this novel posttranslational modification “monoaminylation,” defined as the transamidation-catalyzed formation of a covalent bond between biogenic amines and specific glutamine residues in substrate proteins [90]. Later, in 2003, Michael Bader’s group found that high intracellular serotonin and Ca²⁺ were prerequisites for platelet α-granular secretion and aggregation, implicating TGMs-mediated transamidation in this process [27]. Using ¹⁴C-5-HT labeling, they identified RhoA as a serotonylated target and raised the concept of serotonylation [27]. Concurrently, platelet α-granule proteins including fibrinogen, von Willebrand factor, thrombospondin, fibronectin, and α₂-antiplasmin were shown to undergo TGM2-mediated transamidation [91].

Prior to 2019, identified serotonylated proteins comprised exclusively non-nuclear substrates, which were classified into small GTPases, extracellular polypeptides, and cytoskeletal elements [11]. The paradigm shifted with the discovery that TGM2 catalyzed histone serotonylation, particularly at histone H3 glutamine residues within nucleosomes [92]. Serotonylated histone proteins led to a conformational change of chromosome to an open-state and created a transcriptional permissive environment [92]. This finding built upon earlier observations from 2009. The two-photon microscopy of dorsal raphe serotonergic neurons revealed substantial nonvesicular 5-HT pools [93]. Notably, a significant proportion of this nonvesicular serotonin localized to the nucleus [93]. Photobleaching experiments demonstrated that this nuclear reservoir could freely exchange between nuclear and cytoplasmic compartments [93]. Moreover, serotonin in the nuclear persisted even during activity-dependent vesicular depletion [93]. These data positioned nuclear serotonin as a replenishable buffer for vesicular stores following external stimulation [93]. Nowadays, advances in mass spectrometry have since expanded histone serotonylation studies across tissues and identified numerous nonhistone substrates [4, 94].

“Writer,” “reader,” and “eraser” for serotonylation

TGM2 at a glance

TGM2 belonged to TGM family and was a widely expressed, multifunctional protein that catalyzed covalent cross-linking between glutamine and lysine residues [93]. Beyond its primary transamidation function (Fig. 3), TGM2 exhibited a remarkable functional versatility, serving as a deamidase, GTP-hydrolyzing enzyme, isopeptidase, molecular scaffold, protein disulfide isomerase, and kinase (Fig. 4) [95, 96]. Furthermore, it also modulated posttranslational modification pathways including hypusination and serotonylation [97]. Through these multifaceted activities, TGM2 critically influenced fundamental cellular processes such as proliferation, differentiation, apoptosis, inflammatory responses, tissue regeneration, and fibrotic pathogenesis [95, 97, 98]. This functional versatility stemmed directly from its unique structural organization, which comprised four core domains that coordinately regulated catalytic activity [99].

Fig. 3 — Process of serotonylation catalysis. In environment with a relatively high Ca²⁺ concentration, transglutaminase is maintained in an open state. The γ-carboxamide of the glutamine of targeted proteins and the amino group of serotonin is subsequently covalently linked to form a serotonylated protein. This figure was drawn using the platform of BioRender (https://app.biorender.com/)

Fig. 4 — Calcium-independent activity of TGM2. A In environments with a low Ca²⁺ concentration, TGM2 moves from an open state to a closed state. B TGM2 hydrolyzes ATP to ADP and Pi through its ATPase activity. C TGM2 catalyzes the phosphorylation of targeted proteins, resulting in protein kinase activity. D TGM2 catalyzes the disulfide isomerization reaction as a disulfide isomerase. This figure was drawn using the platform of BioRender (https://app.biorender.com/)

The primary structure of TGM2 could be delineated into the following domains, from the N-terminus to the C-terminus: β-sandwich domain (residues 1–139), catalytic core domain (residues 140–454), and two C-terminal β-parrel domains (residues 455–687 and 688–731) [100]. The β-sandwich domain adopted a β-sandwich fold composed of two anti-parallel β-sheets. It was not part of the direct catalytic core but played a critical regulatory role [101]. The β-sandwich domain was involved in mediating the interaction of TGM2 with fibronectin, facilitating its localization to the extracellular matrix and cell membrane [99, 102]. It also stabilized the protein and enabled large-scale conformational transitions between open and closed states [101]. The catalytic core domain was the heart of the enzyme’s transamidation activity. Its papain-like fold contained the canonical catalytic triad: Cys277, His335, and Asp358. Cys277 was the nucleophilic residue that formed the thioester acyl-enzyme intermediate with the glutamine substrate [99]. His335 and Asp358 activated Cys277 by promoting reactive thiolate anion formation [99]. This domain also coordinated Ca²⁺ and bound the glutamine-donor substrate to prepare for catalytic activation [103]. Additionally, the two tandem β-barrel domains formed a structural unit atop the catalytic core. They were primarily responsible for binding the GTP/GDP [103]. The GTP-binding site lied in a cleft between these two barrels. The first β-barrel (residues 455–687) contained key elements for GTP binding and hydrolysis. The second, smaller β-barrel (residues 688–731) completed the binding pocket [103]. When TGM2 was bound to GTP or GDP, the two C-terminal β-barrel domains packed tightly against the catalytic core domain [100]. This interaction physically occluded the active site and blocked access for protein substrates. In this compact, named as “closed” state, the enzyme was inactive as a TGM but could function as a G-protein in intracellular signaling [104–108].

Molecular mechanism behind TGM2-mediated serotonylation

Serotonylation involved the covalent incorporation of serotonin into glutamine residues of target proteins [91].

The basis of serotonylation was transamindation reaction facilitated by TGMs (Fig. 3). TGMs allowed a covalent bond formed between amines and the glutamine residue of targeted proteins [109]. Similar to other zymogens, TGMs required proteolytic activation to become catalytically competent [110]. To date, eight TGMs (TGM1-7, Factor XIII) have been identified in human, with TGM2 being the most extensively characterized [110, 111]. Genetic evidence supported its physiological relevance. The tgm2-knockout mouse model generated via Cre-LoxP system reduced histone serotonylation level in vivo [31]. However, the tgm1 knockout influenced development and maturation of the stratum corneum in mice [112], although its role in serotonylation remained unconfirmed.

Returning back to TGM2, TGM2’s transamidation activity was dependent on high Ca²⁺ level [98]. The catalytic cycle initiated with His335-mediated deprotonation of Cys277, generating a reactive thiolate anion that attacked the γ-carboxamide of a substrate glutamine [100]. This nucleophilic substitution released ammonia and formed a thioester acyl-enzyme intermediate [100]. During this step, the enzyme underwent a dramatic structural rearrangement to an “open” conformation upon substrate binding and in the presence of high intracellular Ca²⁺ concentrations [100, 113]. This transition involved the realignment of several domains, particularly the movement of the β-sandwich domain and the catalytic core domain, which exposed the catalytic pocket to both the protein–glutamine substrate and the monoamine nucleophile [114, 115].

In this Ca²⁺-stabilized open conformation, serotonin executed a nucleophilic attack on the acyl-enzyme intermediate [100]. Serotonin was bound within a dedicated monoamine-docking site near the active site cleft [100, 116]. While the precise residues defining this pocket were still being mapped, the indole ring of serotonin likely engaged in hydrophobic or π-stacking interactions, while its primary amine group aligned for an in-line attack on the thioester bond [100, 107]. The resulting deacylation of the Cys277 residue broke the thioester link and formed a stable isopeptide bond between the γ-carbon of the protein-bound glutamine and the primary amine nitrogen of serotonin [11, 117]. The final product was a protein covalently modified with a serotonin moiety (a γ-glutamyl-5-HT isopeptide), and the enzyme returned to its ground state [114, 115].

The antagonism between Ca²⁺ and GTP tightly governed the entire process [99]. In the “closed” conformation, GTP/GDP binding at an allosteric site stabilized the inactive state and prevented substrate access [100]. Elevated intracellular Ca²⁺ levels not only promoted directly the open conformation but also competed with GTP for binding, effectively relieving this inhibition [100]. Therefore, TGM2-mediated serotonylation represented a finely tuned interplay between Ca²⁺ activation, GTP inhibition, and precise conformational dynamics that exposed the catalytic triad for sequential transamidation reactions [97, 104, 107, 118].

Besides the “writer” for serotonylation, serotonylated protein could be “read” by several proteins. Notably, the methylation of histone H3 lysine 4, especially its trimethylation (H3K4me3) state, was necessary for transcription initiation [119, 120]. It was asked whether H3K4me3 could influence histone serotonylation at glutamine 5 (H3Q5ser). However, TGM2-catalyzed H3Q5ser occurred independently of this mark [92, 121]. Instead, H3Q5ser influenced the state of H3K4me3 through its own “writers,” “erasers,” and “readers” [121]. The TFIID complex was a key element of the transcriptional preinitiation machinery [122]. Compared with H3K4me3, H3K4me3Q5ser robustly enriched virtually all components of the TFIID complex [92]. This general transcription factor complex, which included TATA-binding protein (TBP) and numerous TBP-associated factors (TAFs), engaged with H3K4me3 primarily through the plant homeodomain (PHD) finger of its TAF3 subunit (reader) [123]. The augmented interaction with the Q5ser-modified histone implied a potential role for this modification to prime transcription through stabilizing TFIID occupancy at promoters and aiding the subsequent recruitment of RNA polymerase II to loci [92, 121, 123]. Moreover, H3K4me3Q5ser completely abrogated lysine-specific demethylase 5B (KDM5B)-mediated H3K4me3 demethylation[121, 124–126]. This finding supported a model wherein the serotonyl group on H3Q5 reinforced permissive transcription by sterically inhibiting key demethylases like LSD1 and KDM5B [121, 126].

WD40-repeat domain of WD-repeat domain 5 (WDR5) was a component of the mixed lineage leukemia 1 (MLL1) complex that positioned the H3 tail for methylation [127]. Independently, another complementary discovery identified the WDR5 as a novel reader for H3Q5ser [127–129]. This was achieved through interaction between the phenylalanine 149 site of WDR5 and N-terminal of serotonylated histone H3 [33, 130, 131]. Notably, H3Q5ser-mediated blockade of KDM5B was strictly dependent on the cis configuration of the dual modification [121]. When H3Q5ser and H3K4me3 were presented as segregated modifications across a population of nucleosomes (in trans), KDM5B was still able to demethylate H3K4me3 [121]. Thus, the inhibitory mechanism was only operative when both marks resided on the same nucleosome particle [121]. In addition, the first PHD finger (PHD1) of several demethylases such as KDM5B, KDM5A was used to identify unmodified H3 and to determine the demethylation of H3K4me3 in the nucleosome [125]. Hence, one question of whether H3Q5ser inhibited the association between PHD1 domain of demethylases and H3 tails was investigated. Sadly, compared with unmodified H3, H3Q5ser only slightly reduced the affinity between PHD1 domain of KDM5B and H3 tails [132]. Similar to this phenomenon, PHD1 domain of KDM5A also tolerated the inhibitory role of H3Q5ser [132]. These confusing results were solved by introducing unmodified H3 with 1–14 residues deleted. Residues 1–14 of H3 were essential for KDM5B activity stimulation [37]. Residue deficiency failed to overcome the inhibition of demethylase activity caused by H3Q5ser, indicating that H3Q5ser-mediated inhibition of H3K4me3 demethylation was dependent on the active state of KDM5B [132].

Recently, the research concerning neural rhythmicity revealed that TGM2 could also function as an “eraser” and “exchanger” for histone H3 monoaminylations [33]. During the circadian rhythm, H3Q5 histaminylation (H3Q5his) and H3Q5ser repelled each other. H3Q5his was erased strictly by TGM2 to allow WDR5 to approach the histone and catalyzing H3K4me3 modification [33]. The elevation in histamine concentration (overdue concentration of serotonin) could prompt TGM2 to erase H3Q5ser and re-write H3Q5his [33]. This finding emphasized the ability of TGM2 to sense the concentration dynamics of monoamines in the surrounding microenvironment. It was unusual for an enzyme to function as both “writer” and “eraser” or “exchanger” in a posttranslation modification type. On this basis, there may be answers for whether serotonylation was irreversible. Transamidation was typically viewed as an irreversible modification [133]. Deamination occurred specifically under conditions where primary amines were insufficient so that water could serve as an alternative substrate owing to its high concentration [134]. Nonetheless, TGM2 and FXIIIa exhibited catalytic versatility because of their isopeptidase activity, which allowed them to dismantle specific transamidation products. This included cleaving ε-(γ-glutamyl)lysyl bridges and hydrolyzing ω-(γ-glutamyl)histaminyl moieties, as observed in celiac disease [135, 136]. Another study revealed that only one residue of the heat-shock protein HSP20 could be deaminated [137]. In several previous studies concerning small GTPases (Rab3A, Rab27A, RhoA), the serotonylation process was consistent and could be halted only by related proteasomal degradation [36]. This observation seemed to define serotonylation as “irreversible.” However, the findings above indicated that serotonylation was actually “reversible,” depending on the concentration differences between serotonin and other monoamines nearby [33].

Although we have obtained a relatively deep understanding of “writer” for serotonylation, our knowledge of its “reader” was poor. The newly developed crosslinking and high-throughput screening strategies used for novel histone modification “reader” characterization [138] may be helpful for identifying more “readers” for serotonylation.

Abundant hypothesis: an update

Owing to the multistate of TGM2 in response to the upstream stimuli, TGM2 played pivotal roles in cell survival, growth, and death [139]. These observations suggested that the primary function of TGM2 was to maintain cellular homeostasis. Thus, TGM2 would use the most applicable sources nearby to catalyze related chemical reaction. In 2023, the “abundant hypothesis” was proposed and discussed in one review [140]. In this hypothesis, the authors noted the following opinions focusing on transamidation. (1) Chemically modified polyamines served as effective substrates for TGM2-mediated transamidation, which displayed a marked selectivity for linear adducts of functional groups compared with their branched counterparts, potentially owing to enhanced reaction kinetics [141]. (2) The enzyme TGM2 functioned as part of an emergency response mechanism to prevent autoproteolysis and programmed cell death. To facilitate this, it engaged indiscriminately with ambient amines, as a selective binding mechanism would compromise the requisite speed of the reaction [140, 141]. (3) Overcoming this binding preference typically necessitated amine concentrations as high as 10 mM to overwhelm the system and achieve incorporation [116, 141, 142]. Given that the serotonylation could also be detected in the organs other than the gastrointestinal tract, it could be inferred that TGM2 may prefer to use serotonin as its substrates and catalyze the transamidation of related proteins [143]. One thing that could not be neglected was that the biosynthetic processes of these amine donors were energetically costly [140, 144, 145], hence the trafficking of serotonin to other regions outside of neural tissue and the gastrointestinal tract was meaningful.

On the basis of recent studies [33], we summarized several new opinions on the “abundant hypothesis.” As mentioned above, TGM2 could also functioned as an “exchanger” and “eraser” for monoaminylation. Importantly, in the absence of alternative monoamine donors, TGM2 removed monoamine adducts and introduced a glutamate residue at the modification site [33]. This process led to a type of protein-mediated mutagenesis that was likely harmful to normal cellular operations. Consequently, the ability of TGM2 to exchange monoamine groups on histone H3 might serve as a key regulatory mechanism for preserving cellular homeostasis when intracellular monoamine levels varied [141]. This observation could support the “nonselective” opinion of the “abundant hypothesis.” In addition, the H3Q5his level increased during the active phase but decreased during rest phase, indicating diurnally rhythmic expression in the mice brain [33]. In contrast, the volatility of histone serotonylation was relatively low [33]. Although further evidences were missing, these observations might indicate that serotonylation was the foundation for the ability of TGM2 to regulate cellular homeostasis. Its “nonselective” feature originated from its ability to sense dramatical changes of other monoamines in the microenvironment if serotonin was missing [33]. Attentionally, organs outside the gastrointestinal tract including the prostate and lungs had their own neuroendocrine cells which could synthesize and secrete serotonin [146, 147]. Thus, serotonin may not need to be trafficked from the gastrointestinal tract. Although the purpose behind this was not clear, a possible explanation may be that serotonin synthesis was relatively easy and stable compared with other amines. Hence, stable serotonylation during the circadian rhythm became their preferred choice.

Methods to detect serotonylation

Methods to detect serotonylation are being updated and becoming easier and more precise.

Direct measurement of serotonin

The most direct way to measure serotonylated protein was to detach bound serotonin from targeted proteins. First, serotonylated fibronectin was purified, and mercaptoethane sulfonic acid was used to hydrolyze serotonin from fibronectin. Hydrolyzed serotonin was detected by high performance liquid chromatography [91]. Although the procedure was easy and direct, this method was advantageous only when the protein was highly expressed and could be easily purified.

Radioactive serotonin

To obtain more obvious results, serotonin could be labeled with H³ or C¹⁴ to yield H³-serotonin and C¹⁴-serotonin. Hence, monoamines incorporated in related proteins could be detected by measuring the radioactivity within precipitates or by autoradiography of gels [27, 28, 32]. However, owing to the relatively low radioactivity of H³ and C¹⁴, this method was not very sensitive.

Biorthogonal-labeled serotonin

Similar to radioactive serotonin, biotinylated serotonin was used for transglutaminase reactions [148]. However, this method faced two problems. First, when biotin was linked to serotonin, the adduct failed to be substrates for TGMs. Second, biotinylated serotonin had a large molecular weight and could not enter cells [12]. Later, biorthogonal-labeled serotonin was invented in which biotinylated serotonin was replaced with a small alkyne-functionalized serotonin, also known as 5-PT [149, 150]. 5-PT could be taken up by cells for the transglutaminase reaction [4]. Afterward, the biotin-residue was linked to the incorporated 5-PT, and biotin-labeled 5-PT facilitated the purification and detection of the serotonylated proteins by either western blotting or mass spectrometry [148].

Corresponding antibodies targeting serotonylated proteins

Peptides containing serotonylated sites could be synthesized and injected to animals. Peripheral blood was then collected and purified to obtain the corresponding antibodies [29, 32, 94, 151–153]. Hence, the serotonylated protein level could be determined via western blotting. However, one unavoidable problem with this method was that cross-reactivity with other nonserotonylated proteins occurred, which may lower the specificity of the corresponding antibodies.

Two-dimensional gel electrophoresis

The basis of this method was that the isoelectric point differed between nonserotonylated proteins and serotonylated proteins. This method was initially used to detect serotonylated fibronectin [151].

Competitive mechanism

In addition to the competitive mechanism of the enzymatic reaction, several researchers have adopted mono-dansylcadaverine or 5-(biotinamido) pentylamine as substrates for the transglutaminase reaction. The advantage of mono-dansylcadaverine or 5-(biotinamido) pentylamine was that they could be easily detected using protein gels or biotin antibodies. When the binding of mono-dansylcadaverine or 5-(biotinamido) pentylamine to target proteins were inhibited by the addition of serotonin, the conclusion could be drawn that the target proteins also underwent serotonylation [92, 154–156]. However, this conclusion was not based on rigorous results, as this experiment provided only indirect evidence. Another problem that has been raised was that mono-dansylcadaverine was sometimes considered to be an inhibitor of transglutaminase activity [12].

Mass spectrometry

To date, mass spectrometry has been the most reliable method for determining serotonylation. When the glutamine residue was attached with serotonin, mass spectrometry could be used to identify the increase in the molecular weight of related peptide fragments [92]. With this method, researchers could enrich proteins that could be serotonylated by immunoprecipitation with an anti-serotonin antibody and determine the exact serotonylated sites with the purified target proteins.

Regioselective rapid ene-type reaction

Recently, a novel method for analyzing the level of histone H3Q5ser using ene-type reaction was proposed. At pH = 4, the regioselective rapid ene-type reaction enabled the transfer of triazolinedione derivatives to the C4 position of 5-hydroxyindole. Hence, the results could be detected using protein gels [157]. This method has been adopted to detect histone H3Q5ser level in the presence of wild-type TGM2 or catalytically-dead (C277A) TGM2 [157].

Chemoselective rapid azo-coupling reaction

To obtain global profiles of serotonylated proteins in cells, an aryldiazonium probe was developed. At pH = 7.6, the probe was labeled to serotonylated proteins via chemoselective rapid azo-coupling reaction [158]. This method was subsequently investigated in the colorectal cancer cell line HCT116, and more than 1000 serotonylated proteins were identified, most of which were related to tumorigenesis [158].

Cleavage under targets and tagmentation

Cleavage under targets and tagmentation, also known as CUT&Tag, was a high-sensitivity epigenomic profiling technique that was optimized for low-abundance histone modifications such as H3Q5ser [31, 148]. Unlike chromatin immunoprecipitation-seqencing, this method avoided cross-linking artifacts and achieved in situ tagmentation within intact nuclei, yielding a > tenfold increase in the signal-to-noise ratios and requiring < 100,000 cells. These advantages made it ideal for mapping rare posttranslational modification [159–161].

Here is a brief description of the workflow of CUT&Tag [159, 162]. Cells were first treated with digitonin (0.01%) to permeabilize the membranes while preserving nuclear integrity. The cells were subsequently incubated with validated anti-H3Q5ser antibody at 4 °C overnight. Notably, during this step, IgG control should be included for background subtraction. The next day, protein A-Tn5 Transposase was preloaded with sequencing adapters (e.g., Illumina). Tn5 bound antibody–protein complexes and cleaved DNA < 20 nm from the H3Q5ser site. DNA was then extracted and PCR was used to amplify the tagmented DNA (5–12 cycles). In sequence, unique dual indices were utilized for multiplexing. Sequence libraries (PE150, 10–20 M reads per sample) were subsequently constructed, and the reads were aligned to the reference genome (e.g., hg38) using Bowtie2. Finally, researchers could call peaks with MACS3. By utilizing CUT&Tag, histone H3Q5ser modification landscapes have been described in cancers such as prostate cancer [30], hepatocellular carcinoma [31], and pancreatic cancer [163].

Single-cell mono-aminylomics

Single-cell monoaminylomics is an emerging frontier in epigenetics that may be used to map histone monoaminylation marks (serotonylation, histaminylation, dopaminylation) across individual cells. This approach resolves cellular heterogeneity in complex tissues (e.g., brain, tumor microenvironment) and reveals how neurotransmitter-driven histone modifications drive cell-type-specific gene regulation. Unlike bulk assays, it captures rare cell states and dynamic transitions in development/disease [13, 33, 164, 165].

This technology involves single-cell cleavage under targets and tagmentation, single-cell assay for transposase-accessible chromatin (ATAC) with monoaminylation integration. Among these, single-cell ATAC with monoaminylation integration aims to examine chromatin accessibility and monoaminylation landscapes and identify cis-regulatory elements co-marked by H3Q5ser. As this technology is evolving, other omics methods such as cellular indexing of transcriptomes and epitopes by sequencing [166] and single-cell RNA sequencing could be included. These methods could better link H3Q5ser peaks with gene expression as well as detect surface and intracellular serotonylation (Fig. 4).

Known targets for serotonylation

Proteins that underwent serotonylation are listed in Fig. 5 and Table 2.

Table 2.

Serotonylated proteins and intracellular processes they are involved in are listed here

Protein name	Category	Site	Cellular processes	References
Histone H3	Histone	Q5	Synaptic remodeling	[132]
			Sensory processing Sensory recovery	[144] [163]
			Organ development Transcription of MYC-related genes State transition of fibroblasts Premature ejaculation Cell fate commitment Neuronal differentiation Stress-related behavior deficits Lipid metabolism Necroptosis Neutrophil extracellular traps formation Liver regeneration	[150] [27] [158] [141] [148] [74] [138] [121] [169] [26] [165]
α/β/ γ-actin	Cytoskeletal proteins	N/A	Contraction of thoracic aorta Colorectal cancer development	[105] [107]
Myosin heavy chain	Cytoskeletal proteins	N/A	Contraction of thoracic aorta	[105]
Filamin A	Cytoskeletal proteins	N/A	Contraction of thoracic aorta	[105]
Fibronectin	Fibronectin	N/A	Pulmonary arterial hypertension Learning and memory formation Extracellular matrix assembly	[192–195] [112] [113]
Rab4	Small GTPase	N/A	Platelets aggregation α-Granules exocytosis Glucose homeostasis	[24] [24] [111]
RhoA	Small GTPase	N/A	Platelets aggregation α-Granules exocytosis Pulmonary arterial hypertension Colorectal cancer development Plasticity and morphology of dendritic spines	[24] [24] [108] [202] [203]
Rab3a	Small GTPase	N/A	Insulin exocytosis	[28]
Rab27a	Small GTPase	N/A	Insulin exocytosis	[28]
Cdc42	Small GTPase	N/A	Plasticity and morphology of dendritic spines	[203]
Rac1	Small GTPase	Q61	Plasticity and morphology of dendritic spines	[203]
Ras	Small GTPase	Q43/Q61	Unknown	[106]
Akt	Other proteins	N/A	Pulmonary arterial hypertension	[204]
SERCA2a	Other proteins	N/A	Sino-atrial node automaticity? Pulmonary arterial hypertension pathway?	[209] [211]
mTOR	Other proteins	N/A	Tryptophan uptake	[212]
PD-L1?	Other proteins	N/A	Immune escape	[213]
GAPDH	Other proteins	Q262	CD8⁺ T cell activation	[4]

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‘N/A’ stands for unidentified serotonylation site. ‘?’ stands for uncertain serotonylation target

Histone

Nucleosomes established the chromatin structure of chromatin [167]. The nucleosome consisted of histone octamer, including H2A, H2B, H3, and H4, as well as the surrounding DNA fragments [168]. Within the histone octamer, non-lysine and lysine posttranslation modifications have been reported and were involved in different intracellular processes including transcription and DNA repair [169].

Among non-lysine posttranslational modifications, one previous study hypothesized that histones H2A, H2B, H3, and H4 were substrates for TGM2-catalyzed reaction [170]. However, one recent study reported that histone H3, but not other histones, was indeed serotonylated at its Q5 residue [92].

Histone serotonylation could fulfill its role alone or through crosstalk with other histone posttranslational modifications. First, there was a bidirectional crosstalk between neurons and tumorigenesis in the brain [171]. The neuromodulator secreted by neurons could regulate the epigenome in brain tumors. Among supratentorial ependymoma patients, approximately 70% of patients displayed ZFTA–RELA fusion, which resulted in more aggressive tumors than ependymomas with no ZFTA–RELA fusion [172, 173]. Immunochemical staining revealed that SERT expression was greater in ependymoma patients with ZFTA–RELA fusion than in patients with no ZFTA–RELA fusion [174], highlighting the significance of serotonin in the aggressiveness of ependymoma through the SERT-mediated pathway. Notably, one distinguishing characteristic of ependymoma was that it highly relied on epigenomic dysregulation [175]. These findings suggested that serotonin secreted by serotonergic neurons could promote ependymoma progression by increasing the level of histone serotonylation [174]. This could lead to increased transcription of ETS translocation variant 5 (ETV5) [174]. ETV5 reshaped repressive chromatin states to inhibit the transcription of neuropeptide Y, which could suppress ependymoma via synaptic remodeling at the peritumoral margin [174]. An interesting question following above finding was whether combining a SERT inhibitor and neuropeptide Y could achieve anti-ependymoma effects. Although the injection of serotonin into newborn mice could cause ependymoma [176], the precise relationship between serotonin receptor-mediated signaling and SERT-mediated signaling was unknown.

Moreover, chronic stress could increase the incidence of mood disorders, especially depression [177]. Previous studies showed that the dysfunction of serotonin receptor (e.g., 5-HTR1A)-mediated signaling in the synapse contributed to depression symptoms, and these findings hastened the development of serotonin-associated antidepressants [178–180]. However, the low remission rate and the obvious delay between specific treatment and symptoms alleviation prompted the researchers to hypothesize that serotonin played other biological roles in depression that were independent of classical serotonin receptor-mediated signaling [181]. Interestingly, chronic stress could epigenetically increase the degree of histone serotonylation in the dorsal raphe nucleus and create transcriptionally permissive conditions to increase the transcription of stress-related genes [182]. Using fluoxetine or viruses to disrupt histone serotonylation could attenuate chronic stress-mediated depression behavior [182]. In addition, premature ejaculation was another disease that bothered male patients. Ejaculation is a process that is strictly regulated by the ejaculation center in the brain, which is sensitive to serotonin [183]. The effects of serotonin could mediate ejaculation through the balance between 5-HTR1A/1B- and 5-HTR2C-mediated signaling [183]. Additionally, the dopamine D4 receptor was essential because it delayed ejaculation [184]. Under these conditions, histone serotonylation delayed premature ejaculation through the transcriptional activation of dopamine D4 receptor, and dopaxetine was a potential therapeutic agent for increasing histone serotonylation [185].

In addition to the pathological function of histone serotonylation in nervous system diseases, it could also have physiological function in the nervous system. Neuronal activity and neurotransmission were critical in the nervous system, where the linkage between astrocytes and neurons executed by neurotransmitters played essential roles in the above processes [186]. Mechanistically, astrocytes expressed receptors for these neuromodulators including serotonin, noradrenaline, and acetylcholine [187]. Recently, serotonin transporter solute carrier family 22 member 3 (SLC22A3) in astrocytes was shown to mediate communication between astrocytes and neurons [188]. In particular, neuronal activity increased the secretion of serotonin. SLC22A3 transported serotonin into astrocytes to induce histone serotonylation level. This led to elevated transcription of gaba and the release of γ-aminobutyric acid (GABA) with the aim of ensuring appropriate sensory processing [188]. In addition to the serotonin transporter, the serotonin receptor, especially 5-HTR2B, could sense serotonin and caused calcium oscillation, leading to the secretion of ATP, glutamate and d-serine into the microenvironment [74]. This effect regulated synaptic transmission efficiency and formed a astrocyte–neuron circuit [74]. Cellular reprogramming was important in the nervous system in which epigenetic rearrangement created a favorable environment for the intrinsic plasticity of brain cells [189]. Among the stimulants that influenced cell fate decisions, serotonin could inhibit the proliferation and promote the differentiation of neural stem cell through 5-HTR1A signaling, whereas 5-HTR2A inhibited the excessively early differentiation of the neural stem cell [190, 191]. In addition, serotonin-induced histone serotonylation was enriched in euchromatin, whose expression was significantly elevated during cell differentiation, and this process was sensitive to the balance between histone acetyltransferase activity and histone deacetylase activity [92, 192]. The resulting oscillation of the transcription process by histone serotonylation primed cells for a long-lasting fate transition [192].

Moreover, histone serotonylation also played a role in non-nervous system. The placenta was the connection between maternity and fetus that was necessary for the organismal and embryonic/fetal development [193]. Serotonin played a role throughout the lifespan of the placenta, starting with placental formation and proceeding with subsequent fetal development [194]. Serotonin receptor-mediated signaling was involved in angiogenesis, vesicular contraction, as well as the migration and invasion of trophoblast cells [194]. Histone serotonylation promoted placental growth, which could explain why patients who took selective serotonin reuptake inhibitors could have smaller babies [195, 196]. However, the influx of serotonin into cytotrophoblasts through SERT and the induction of histone serotonylation may have some negative effects [196]. Although transcriptional plasticity (e.g., that of neurodevelopmental genes) could promote embryonic/fetal growth or brain growth, excessive serotonylation may lead to the development of autism [196, 197]. In turn, histone serotonylation played a role in pathological diseases involving the non-nervous system. The liver was the source of and storage site serotonin [198]. Liver injury could induce the release of serotonin from platelets distributed in the perisinusoidal space and promote tumorigenesis [199, 200]. 5-HTR2A and 5-HTR2B were two critical serotonin receptors whose expression was increased in hepatocellular carcinoma [201]. Serotonin bound to 5-HTR2A and 5-HTR2B activated the downstream signaling cascade, which induced cancer cell growth and inhibited apoptosis [202, 203]. In parallel, SERT and TGM2 were also significantly expressed in hepatocellular carcinoma [31]. Specifically, TGM2 had the potential to be a novel prognostic biomarker for hepatocellular carcinoma in that high tgm2 transcription level was associated with elevated alpha-fetoprotein levels, poor tumor differentiation, advanced Barcelona Clinic Liver Cancer stages, and reduced overall survival and disease-free survival [31]. Serotonin induced histone serotonylation through SERT in hepatocellular carcinoma to activate the transcription of MYC-related genes. This effect could also promote the progression of hepatocellular carcinoma [31]. Mechanistically, TRIM28 guided the association between TGM2 and MYC to induce histone serotonylation. Establishing a liver-specific tgm2-knockout mouse model or administering the TGM2 inhibitor GK921 yielded ideal antitumor effects [31]. Colorectal cancer was another type of gastrointestinal tumor that was sensitive to serotonin [21]. However, colorectal cancer seemed to be insensitive to serotonin-receptor mediated signaling because tropisetron (5-HTR3 antagonist) and SB269970 (5-HTR7 antagonist) had no significant antitumor effects on colorectal cancer [204]. In contrast, histone serotonylation promoted colorectal cancer progression as knockdown of the serotonin transporter slc22a3 or treatment with the TGM2 inhibitor GK921 significantly inhibited tumor growth [204]. Interestingly, histone serotonylation did not act on cancer cells themselves but acted on the surrounding cancer-associated fibroblasts to promote state transition toward an inflammatory state [204]. Hence, histone serotonylation could function as an indicator for epithelial–mesenchymal transition in colorectal cancer [204].

Owing to the close spatial proximity, there could be crosstalk between H3Q5ser and H3K4me3 or histone H3 citrullination (H3cit), resulting in H3K4me3Q5ser modification [92] and H3R2citQ5ser modification [30], respectively (Fig. 6). In the central nervous system, H3K4me3Q5ser primed neuron differentiation parallel to serotonin receptor-mediated signaling [92]. Chronic stress upregulated H3K4me3Q5ser dynamics to induce behavioral deficits [182]. In the peripheral nervous system, serotonin was pivotal for tissue regeneration such that axonal regeneration was achieved, and neural function was partially restored [205, 206]. Through serotonin receptor-mediated signaling, serotonin induced the state transition of Schwann cells toward the repairing state (5-HTR2B) and the extension of injured axons (5-HTR1A) [207, 208]. Independent of this pathway and using lip sensory recovery as an example, TGM2 and H3K4me3Q5ser level increased within primary neurons from trigeminal ganglia in response to nerve transection [209]. This effect influenced the transcriptional landscape to increase the transcription of genes related to axonal growth and neurotrophic factor regulation [209]. However, the TGM2 inhibitor GK921 blocked H3K4me3Q5ser-induced nerve recovery [209]. Combining the H3K4me3Q5ser-mediated pathway and serotonin receptor-mediated pathway may further lead to nerve repair after injury.

Fig. 6 — Crosstalk between histone serotonylation and other histone posttranslational modifications. A Histone serotonylation occurs at the Q5 site of the histone H3 chain. B Histone citrullination occurs at the R2 site of the histone H3 chain and is catalyzed by PAD4. Crosstalk between PAD4 and TGM2 increases both histone citrullination and histone serotonylation. C Histone methylation occurs at the K4 site of the histone H3 chain. The serotonylation of histone inhibits the binding of KDM5B/C and LSD1 to the K4 site but enhances the binding of WDR5/MLL1 and TAF3 to the K4 site, maintaining the histone methylation level of the K4 site. D During the circadian rhythm, histone serotonylation and histone histamination are catalyzed by TGM2. However, these two types of histone modifications repel each other to maintain oscillation of the transcription process. This figure was drawn using the platform of BioRender (https://app.biorender.com/)

Among non-nervous systems, serotonin level was greater in pancreatic ductal adenocarcinoma [210]. Serotonin interacted with 5-HTR2B and activated PI3K/AKT/mTOR signaling cascade to enhance glycolysis in cancer cells [211]. Using the 5-HTR2B inhibitor SB204741 diminished tumor growth [211]. In parallel, TGM2 and H3K4me3Q5ser were found to be highly expressed in pancreatic ductal adenocarcinoma and were associated with poor overall and disease-free survival [163]. These findings indicated that TGM2 and H3K4me3Q5ser may serve as independent prognostic factors [163]. H3K4me3Q5ser induced transcription of stearoyl-CoA desaturase to remodel lipid metabolism. Genetic or pharmacological blockage of TGM2 could decrease H3K4me3Q5ser level and tumor growth [163]. Additionally, the enzymatic activity of TGM2 was a critical determinant of the ability of the liver to regenerate after enduring chronic toxic injury [212]. A key regenerative mechanism involved the ductular reaction, which was characterized by robust expansion and phenotypic remodeling of the cholangiocyte compartment [213]. TGM2 served as a cornerstone of this reparative program and drove the tissue-level changes necessary for successful hepatic recovery from cholestasis [212]. During this process, TGM2 increased the expression level of H3K4me3Q5ser to promote the activation of BMP (bmp2, bmp6, bmp7, bmp8a) signaling [212]. Activated BMP signaling facilitated the development and maturation of cholangiocytes [212]. However, tgm2-knockout mice failed to recover after exposure to toxins [212]. Under these conditions, the serotonin receptor (5-HTR2A/2B/2C)-mediated signaling cascades induced cell proliferation, and the related signaling activation was positively involved in ductular reaction [214]. Among physiological processes, H3K4me3Q5ser was observed to control necroptosis, which was a caspase-independent pathway of programmed cell death [215]. Necroptosis resulted in a lytic manner of cellular demise, which was marked by plasma membrane disintegration [216]. Related molecular characteristics were governed by a precise signaling pathway that converged on the activation of the executioner protein receptor interacting protein kinase 1 and receptor interacting protein kinase 3 (RIPK3) [217]. Interestingly, the transcription of ripk3 was highly dependent on the H3K4me3 level within its promoter [218], making it sensitive to other histone modifications near the H3K4 site. In mouse embryonic fibroblasts, RIPK3 expression was absent when the cells lost TGM2 expression [219]. This finding suggested that TGM2 mediated RIPK3 expression through H3K4me3Q5ser-induced transcriptional activation [219]. However, serotonin receptor-mediated signaling via 5-HTR4 had the opposite effect and inhibited necroptosis through reducing RIPK3 expression [220].

In addition to dual H3K4me3Q5ser modification, dual H3R2citQ5ser modification could also occur. H3R2citQ5ser was induced through crosstalk between TGM2 and PAD4 in neutrophils [30]. Unlike H3K4me3Q5ser, H3R2cit and H3Q5ser were mutually conditional [30]. This phenomenon was observed in neuroendocrine prostate cancer-induced liver metastasis. Prostate cancer could progress from the castration-sensitive type to the castration-resistant type and, ultimately, to the neuroendocrine type [221]. Neuroendocrine prostate cancer cells could secrete serotonin [222]. After neutrophils take up serotonin, TGM2 could modify the H3Q5ser within the promoter [30]. The increase in H3Q5ser could recruit PAD4 and enhance H3R2cit. In turn, H3R2cit could recruit TGM2 to modify H3Q5ser, resulting in the formation of a positive circuit [30]. The resulting formation of neutrophil–extracellular trap formation further promoted cancer progression [30]. However, the TGM2 inhibitor GK921 and the SERT inhibitor fluoxetine inhibited the formation of the neutrophil–extracellular trap induced by serotonin [30]. In this case, castration-resistant prostate cancer was sensitive to serotonin [223]. With respect to serotonin receptor-mediated signaling, 5-HTR1A was highly expressed and activated the AKT/mTOR signaling pathway [224]. With respect to histone serotonylation, our group reported that TGM2 could catalyze H3K4me3Q5ser within promoter of targeted genes, leading to the progression of castration-insensitive prostate cancer (under review).

Taken together, these results revealed that histone serotonylation mainly regulated the chromatin state to influence transcription processes. Histone serotonylation and other types of histone modifications usually worked together and coexisted to further modulate transcription activation.

Cytoskeletal proteins

Cytoskeletal proteins were located below the cell surface and underwent dynamic modulation to ensure proper cell conformation and motility [225]. Typically, cytoskeletal dynamics could be stimulated by serotonin receptor-mediated signaling cascades [226]. For example, in smooth muscle cells from vasculature, serotonin interacted with 5-HTR2A and activated RhoA/ROCK signaling pathway [227–229], leading to the hyperphosphorylation of actin and myosin, which were responsible for strong vascular contraction [230]. Bearing this idea in mind, it was asked whether serotonin could directly impact cytoskeletal proteins to achieve more precise function. Among most proteins that could be serotonylated, glutamine residues accounted for 2–3% of the whole amino acid sequence [148, 150]. Surprisingly, the myosin heavy chain contained up to 6% glutamine residues, indicating that it had great potential to be serotonylated [148, 150]. Following this finding, the serotonylation of cytoskeletal proteins was observed during vascular contraction [148]. According to mass spectrum analysis, cytoskeletal proteins including α/β/γ-actin, myosin heavy chain, and actin-binding protein filamin A were found to be serotonylated in rat-derived aortic smooth muscle cells [148]. α-Actin was further proved to be serotonylated via an antibody against serotonin [148]. The 5-HT-stimulated contraction of the thoracic aorta could be blocked by the TGM2 inhibitor cystamine, further supporting the hypothesis that serotonylation also participated in the contraction process [148]. Interestingly, serotonylation of actin also occurred in nonvascular tissues including the small intestine, stomach fundus, and cerebral cortex [148]. Apart from normal tissues, serotonylated actin may potentiate colorectal cancer progression, as supported by mass spectrum data [150]. Further studies could explore the precise serotonylated sites of cytoskeletal proteins and the exact function of serotonylation in the regulation of cytoskeletal dynamics, especially the crosstalk between serotonylated actin and acetylated microtubules.

Fibronectin

Fibronectin was a glycoprotein detected in blood, in connective tissue, and on the cell surface [231]. The classical function of fibronectin involved attaching cells to the surrounding extracellular matrix [232]. Pulmonary arterial hypertension was a severe, progressive, and life-threatening disorder characterized by high blood pressure in the pulmonary arteries [233]. Serotonin signaling was significantly amplified during pulmonary arterial hypertension, which could be attributed to two aspects. First, endothelial injury in the pulmonary arteries was the initiating event in pulmonary arterial hypertension [234]. At the site of injury, platelets were activated, aggregated, and released large quantities of stored serotonin, creating a local environment of concentrated serotonin [235]. In addition, activated pulmonary arterial endothelial cells and smooth muscle cells upregulated their own capacity to synthesize serotonin [236]. This created autocrine and paracrine loops, further exacerbating local serotonin signaling [235, 236]. Serotonin receptor-mediated signaling cascades promoted intense pulmonary vasoconstriction (5-HTR1B) and drove pulmonary vascular remodeling and occlusion (5-HTR2A, 5-HTR2B) [237–240]. Interestingly, certain polymorphisms within the slc6a4 gene were positively correlated with increased susceptibility to pulmonary arterial hypertension [241]. The knockout of slc6a4 in mice prevented them from developing pulmonary arterial hypertension upon exposure to hypoxia [242]. In contrast, SM22-stimulated promoter activation could enhance slc6a4 transcription and led to pulmonary arterial hypertension in mice [243]. These results indicated a potential role for serotonin in pulmonary vascular remodeling that was independent of the serotonin receptor-mediated pathway. It was proved that intracellular serotonin led to the proliferation of pulmonary vascular smooth muscle cells [244, 245]. Treating pulmonary arterial hypertension smooth muscle cells in culture with serotonin increased the serotonylation of multiple proteins [246]. One of these proteins that was predominantly serotonylated was fibronectin [246, 247]. Fibronectin, especially serotonylated fibronectin, promoted pulmonary arterial hypertension through establishing a scaffold for cell migration and invasion [248]. Recruited cytokines could create a highly proliferative environment and increase the sensitivity of the vasculature to vasoconstrictors [232, 246–248]. However, the genetic or pharmacologic inhibition of TGM2 blocked the serotonin-induced proliferation and migration of smooth muscle cells [246, 247]. Bearing these cellular findings in mind, mice and rats with pulmonary arterial hypertension produced via exposure to hypoxia or injection of monocrotaline could increase serotonylated fibronectin level in the lungs and blood, which could reflect the elevated activity of TGM2 [246, 247, 249]. Additionally, patients with pulmonary arterial hypertension also had an elevated ratio of serotonylated fibronectin/fibronectin (0.3 ± 0.18 versus 0.05 ± 0.07) [248]. These results suggested that serotonylated fibronectin could serve as a novel marker for the detection or prognostic evaluation of pulmonary arterial hypertension.

Additionally, in the nervous system, serotonin was transferred to fibronectin in C6 glioma cells [154]. Herein, serotonylated fibronectin stabilized the extracellular matrix to aggregate adjacent cells, which was helpful for learning and memory formation [154]. Conversely, when osteoblasts attached serotonin to fibronectin, serotonylated fibronectin assembled the extracellular matrix with less efficiency through curbing mineral deposition in the culture [155]. Unexpectedly, the transamidation of serotonin to fibronectin was not conducted by TGM2 but by factor XIIIa in osteoblasts, highlighting the heterogeneity of serotonylation in different cell types [155]. Moreover, mass spectrometry or monodansylcadaverine (MDC) administration followed by mass spectrometry revealed 3 or 11 glutamine residues that were prone to be serotonylated, respectively [28, 149]. This fact highlighted the urgency of conducting site mutation experiments and identifying the exact serotonylation sites that contributed to fibronectin function.

Small GTPases

Small GTPases belong to the Ras superfamily [250]. In essence, small GTPases were guanine-nucleotide-dependent switches that modulated related cellular processes including cell proliferation, cell motility, cell adhesion, and so on [251, 252]. Typically, these GTP-dependent proteins were strictly regulated by guanine nucleotide exchange factors, GTPase activating proteins, and guanine nucleotide dissociation inhibitors [253]. However, covalent conjugation by monoamines, including serotonin, rendered GTPases constitutively catalytically active whatever in their GDP- or GTP-bound form [36]. This phenomenon effectively uncoupled signaling outputs from the regulatory constraints of nucleotide binding and hydrolysis.

In platelets, two small GTPases, namely, the Ras-related protein Rab4 (Rab4) and the transforming protein RhoA (RhoA), were serotonylated by TGM2 [27]. The serotonylated Rab4 and RhoA conferred them with constitutive activity to interact with downstream signaling molecules and induce platelet aggregation [27]. Additionally, serotonylated Rab4 and RhoA promoted cytoskeletal rearrangement and α-granule exocytosis in platelets [27]. Similarly, in pancreatic β-cells, glucose uptake through glucose transporter 2 (GLUT2) caused a sudden increase in Ca²⁺ concentration within the cytoplasm, which drove TGM2 to catalyze the serotonylation of two small GTPases, Rab3A and Rab27A, resulting in their constitutive activation to increase insulin exocytosis [32]. Interestingly, the translocation of GLUT4 to the plasma membrane was an important component of the insulin signaling pathway which was partially mediated by small GTPases [254]. Whether the serotonylation of small GTPases truly influenced GLUT4 translocation deserved to be investigated. Moreover, although whether TGM2 mediated the serotonylation of Rab3A and Rab27A was unclear, present evidence indicates that TGM2 indeed maintained insulin secretion [32]. On the one hand, abrogating TGM2 activation using MDC impaired insulin secretion and led to glucose intolerance [255]. On the other hand, mutations in TGM2 were also correlated with early onset of type II diabetes [256]. Furthermore, the serotonylation of Rab4 in skeletal muscle cells explained the typical mechanism underlying how glucose was transported and how glucose homeostasis was maintained [153].

In addition to its roles in regulating insulin secretion and platelet aggregation, serotonylation was involved in other cellular processes. Returning to pulmonary arterial hypertension, the degree of RhoA serotonylation was increased in the smooth muscle cells, platelets, and lungs of patients [29, 151]. The inhibition of TGM2 or serotonin transporter alleviated serotonylation of RhoA. This resulted in reduced smooth muscle cell contractility to alleviate pulmonary arterial hypertension [151]. In colorectal cancer cells, TGM2-mediated RhoA serotonylation activated Rho-associated protein kinase 1/2 signaling to increase the expression of Yes-associated protein homolog 1, enabling cancer cell proliferation [257]. In addition, cell division control protein 42 homolog (Cdc42), Rac1 and RhoA underwent serotonylation in dendritic spines to promote actin dynamics and guarantee normal plasticity and morphology [258]. Unexpectedly, the serotonylation of Rac1 occurred through the 5-HTR2A/TGM2 axis, but not the SERT/TGM2 axis [94]. The 5-HTR2A agonist 2,5-dimethoxy-4-iodoamphetamine significantly increased the serotonylation of Rac1 [94]. Although it may seem unusual, a possible explanation was that the activation of 5-HTR2A led to an increase in the intracellular Ca²⁺ concentration to prime TGM2 activity. Building on this idea, both G protein-coupled receptors and ligand-gated ion channels could allow transamidation and Rac1 serotonylation to occur, ultimately reshaping the size of dendritic spines [94]. Further investigation using site mutation revealed that Rac1 was serotonylated by TGM2 at Q61, a site located in the GTP-bound region [94]. Q61-serotonylated Rac1 was constitutively activated and led to the sustained activation of downstream signaling pathways [27]. Another well-known small GTPase, Ras, was also serotonylated [149]. Although the function of serotonylated Ras was unknown, mass spectrometry demonstrated that Ras was serotonylated at Q43 and Q61 [149], suggesting that serotonylation may influence the GTP-binding activity of Ras.

Serotonylated small GTPase have been better researched. However, our knowledge of serotonylation in small GTPases was limited to the opinions that serotonylated small GTPases usually owned redundant activation. Given that small GTPases were involved in various physiological and pathological processes [259], further investigations could focus on revealing novel functions of serotonylated small GTPase and how to target serotonylated small GTPase in interfering diseases.

Other proteins

In addition to the above serotonylated proteins, other proteins could be serotonylated. Pulmonary arterial hypertension development required pulmonary vascular remodeling in which 5-HT induced pulmonary artery smooth muscle cell proliferation [233, 260]. During this process, TGM2 induced the serotonylation of Akt, subsequently activated downstream signaling cascades and promoted pulmonary artery smooth muscle cell proliferation [260]. Moreover, normal cardiac function was partially dependent on serotonin signaling, especially in the sinoatrial node [261]. The sinoatrial node highly expressed 5-HTR4 and activated cAMP signaling to increase pacemaker currents [262, 263]. Moreover, with respect to the intracellular aspects, normal cardiac function was guaranteed by sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase (SERCA) to maintain energy balance [264]. Abnormal Ca²⁺ ATPase activation resulted in sinoatrial node automaticity [265]. One previous study isolated cardiomyocytes from patients with sinoatrial node automaticity and reported that SERCA2a was serotonylated [266]. However, the link between SERCA2a serotonylation and sinoatrial node automaticity has not been elucidated. Recently, the function of serotonylated SERCA2a was investigated in human pulmonary artery venous smooth muscle cells [266]. The serotonylation of SERCA2a inhibited its activity and enhanced Ca²⁺ influx via the short transient receptor potential channel 6 [267]. Although the exact effectors were unknown, 5-HT-mediated serotonylation allowed mammary gland involution, as the TGMs inhibitor mono-dansylcadaverine blocked this effect [268].

The activity of mammalian target of rapamycin (mTOR) was dependent on its serotonylation [269]. Targeting SERT suppressed mTOR serotonylation and downstream S6K signaling activation [269]. Serotonylation also weaken the immunotherapy effect in hepatocellular carcinoma as 5-HT increased the expression of programmed cell death 1 ligand 1 (PD-L1) in cancer cells, which could be blocked by the TGM2 inhibitor iodoacetamide [270]. It was possible that ubiquitin-mediated protein degradation participated in this process. Additionally, serotonylation also occurred in immune cells. In CD8⁺ T cells, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was serotonylated at Q262 by TGM2 without influencing its catalytic activity [4]. Instead, the serotonylation site lied in its nuclear-export signal and Q262 serotonylation facilitated the cytoplasmic-localization of GAPDH [4]. This effect promoted glycolysis in CD8⁺ T cells and conferred them with antitumor capability.

Summary

Considering that protein serotonylation occurred in both nonimmune and immune cells, further investigations could explore the function of protein serotonylation in other types of immune cells. Recently, the concept of nanotubes was proposed [271]. Nanotubes mediated intracellular crosstalk through the transfer of RNA, proteins, and organelles [271–273]. Hence, whether serotonylated proteins could be transferred through nanotubes between different types of cells should be investigated because the degree of catalytic competence of serotonylation varied across different types of cells.

Relationship between serotonin receptor-mediated signaling and SERT-mediated serotonylation

Although serotonin receptor-mediated signaling and SERT-mediated serotonylation were seemingly independent of each other, these two pathways in essential were regulated by the same signaling molecule, serotonin, and the crosstalk between them indeed existed. Classically, the activation of the serotonin receptor-mediated signaling pathway stimulated the PKA or PKC cascade [21]. PKC, for example, could phosphorylate SERT and lead to the internalization of SERT, achieving short-term regulation [274, 275]. In addition, second messengers downstream of PKA signaling could influence the activation of transcription factors such as CREB to regulate slc6a4 transcription, resulting in long-term regulation [276–278]. Unlike the classical crosstalk mechanism, elevated plasma serotonin stimulated the phosphatidylinositol pathway via 5-HTR2A in platelets to increase intracellular Ca²⁺ levels and thereby activated TGM2 [27, 279, 280]. This enzyme then facilitated the serotonylation of small GTPases. Among small GTPases, Rab4 could interact with SERT. The serotonylation of Rab4 could restrict the intracellular localization of SERT by modulating actin dynamics [19, 78, 281, 282]. These findings led us to hypothesize that the serotonin receptor-modulated signaling pathway could downregulate the plasma membrane localization of SERT and that this process may be mediated by serotonin receptor-induced serotonylation. However, whether serotonylation could in turn regulate serotonin receptor-mediated signaling was unknown. This effect may be mediated through regulating serotonin receptor internalization or targeting critical signaling molecules downstream of serotonin receptor.

Strategies to target serotonylation

As highlighted above, serotonylation played critical roles in pathological processes such as pulmonary arterial hypertension, diabetes, and metastatic prostate cancer. The development of strategies to target serotonylation had the potential to treat related diseases. In accordance with the catalytic process of serotonylation, strategies have been developed to target serotonin synthesis, serotonin reuptake, and TGM2 activity (Fig. 7, Table 3).

Fig. 7 — Strategies for targeting serotonylation. A Selective serotonin reuptake inhibitors (SSRIs) have been developed to target SERT with the aim of blocking serotonin reuptake. B Blocking TGM2 transglutaminase activity reduces the degree of serotonylation of targeted proteins. C The production of serotonin requires TPH-1 and TPH-2 catalysis. Hence, inhibiting its activity is meaningful. Current TPH inhibitors could not discriminate between TPH-1 and TPH-2. D–F Strategies proposed in this review. D CAR-T cells have high specificity and high effectiveness. Editable CARs targeting SERT or TPH may improve the efficiency to block serotonylation. E The cell surface localization of SERT is a prerequisite for serotonylation. Impairing the process through which the SERT is translocated from Golgi apparatus to plasma membrane may have some clinical values. F Crosstalk between histone serotonylation and other histone modifications occurs. Combined therapy targeting multiple types of histone modifications may offer some clinical significance. This figure was drawn using the platform of BioRender (https://app.biorender.com/)

Table 3.

The structures of potential inhibitors that targeting serotonylation

Name/target	Inhibitor chemical class	References
LX-1606/TPH	Telotristat	[235]
Cystamine/TGM2	Disulfide	[253–255]
GK921/TGM2	Pyrazine	[256–261]
Fluoxetine/SERT	Benzodioxole	[25, 26, 241]
Citalopram/SERT	Benzofurancarbonitrile	[241]
Escitalopram/SERT	Benzofurancarbonitrile	[241]
Paroxetine/SERT	Benzodioxole	[241]
Sertraline/SERT	Tetralin	[241]

Open in a new tab

The structures are derived from PubChem (https://pubchem.ncbi.nlm.nih.gov/)

Blocking serotonin synthesis

Serotonin was the substrate for serotonylation, and a distinguished TGM2 activity was dependent on high serotonin level [98]. Evidences from previous studies showed that tph1-knockout protected mice against thrombosis through prolonging bleeding time [27]. The mechanism underlying this phenomenon was that tph1 deprivation decreased the serotonylation of Rab3a and Rab27a [32]. In the prostate cancer microenvironment, 5-HT was synthesized by TPH-1 in neuroendocrine prostate cancer cells [30, 283]. Silencing tph1 in neuroendocrine prostate cancer cells could reduce prostate cancer proliferation and regeneration [283]. Other pathological processes that could be treated through blocking serotonin synthesis included diabetes, fibrosis, obesity, inflammation, and so on [43].

Drugs targeting TPH isoforms mainly blocking their tryptophan pocket [284]. Initially, two phenylalanine analogs p-chlorophenylalanine and p-ethynylphenylalanine were used to treat patients with carcinoid syndrome [285–287]. Although clinical use demonstrated the expected effects, the fact that these two drugs could also inhibit the activity of other enzymes and the transport of tryptophan within neurons precluded them further use in clinical practice [288, 289]. Later, Lexicon Pharmaceuticals, Inc. developed several phenylalanine derivates with the help of high-throughput screening. All these derivatives could inhibit both isoforms of TPH with the same efficiency and avoid penetrating the blood–brain barrier [290, 291]. As a result, the central serotonin level was not influenced, which presented some side effects [291]. The FDA approved telotristat ethyl (LX-1606) as the first TPH inhibitor for treating patients with carcinoid syndrome diarrhea [292]. Karos Pharmaceuticals, Inc. further constructed a new scaffold and developed spirocyclic proline-based but not phenylalanine-based compounds [293, 294]. Related clinical trials have been initiated.

The ubiquitous disadvantage of the presently available TPH inhibitors was that they could not differentiate between TPH-1 and TPH-2 [295]. Recently, two compounds considered to be selective TPH-1 inhibitors were screened [296, 297]. However, their efficacy required further determination in clinical trials.

Blocking SERT

The main function of SERT was to regulate the reuptake of serotonin. Owing to this characteristic, SERT has become a promising target for treating depression [298]. The most well-known SERT inhibitors were selective serotonin reuptake inhibitors (SSRIs), which included fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram [299]. The affinity between SSRIs and SERT was approximately 10–100 times greater than that between SSRIs and other neurotransmitter transporters or receptors [300]. The molecular structure of these SSRIs was similar to that of 5-HT [301]. The binding of SSRIs to SERT blocked the central pocket of SERT and isolated 5-HT from SERT [301]. Additionally, the binding of SSRIs locked SERT in the inward-facing state but not in the outward-facing state so that 5-HT failed to be transported into cells [302]. After SSRI treatment, the accumulation of 5-HT within the brain was observed [303]. Although the exact effects of SSRIs on SERT were controversial, several obvious changes were detected under SSRIs treatment. For instance, increases or decreases in sert mRNA was observed in the dorsal raphe nucleus [304]. Additionally, the internalization or degradation of SERT in the dorsal raphe nucleus were found [304].

In addition to their traditional roles in the nervous system, SSRIs also influenced peripheral tissues. For instance, the SSRI fluoxetine inhibited the serotonylation of RhoA and relieved pulmonary arterial hypertension [29]. Fluoxetine also reduced neutrophil extracellular trap formation in metastatic prostate cancer through targeting histone serotonylation in neutrophils [30]. In addition, 5-HT accumulation in the tumor microenvironment after fluoxetine treatment activated 5-HT/5-HT receptor/MAPK signaling to increase T-cell antigen receptor (TCR) expression in CD8⁺ T cells, prompting their antitumor effects [305].

SERT was produced in the endoplasmic reticulum and transported to the Golgi apparatus to be packaged into vesicles [306]. One previous study revealed that vesicle-associated membrane protein 2 (VAMP2) participated in the cell surface localization of SERT [307]. Hence, targeting the transportation of SERT may constitute another strategy. In addition to SERT, other transporters, such as organic cation transporters, were also capable of transporting serotonin, but to a lesser extent [308]. Whether targeting these transporters cold achieve some effects deserved to be investigated.

Blocking TGM2

TGM2 was widely acknowledged for its role in serotonylation catalysis. Hence, targeting TGM2 was promising and rational. TGM2 used its TGM activity instead of its GTPase activity to affect the pathogenesis of diseases including heart failure, tumorigenesis, inflammatory disease, and neurodegenerative disorders [309–311]. Evidences from many studies supported the concept that targeting transglutaminase activity was meaningful [11]. In neurodegenerative disorders and hepatocellular carcinoma, the genetic abrogation of transglutaminases slowed down the progression of related pathological manifestations and reduced the number of metastatic nodules in the lungs, respectively [31, 312].

Current inhibitors of TGM2 could be divided into two types, namely, reversible and irreversible inhibitors. The irreversible inhibitors included 3-halo-4,5-dihydroisoxazole inhibitors, halomethyl carbonyl inhibitors, michael acceptors, and sulfonium inhibitors [313]. However, their effects in animal models and clinical trials were unknown. Cystamine was a reversible inhibitor that achieved ideal effects in vitro and in vivo [314]. Specifically, cystamine was reduced to cysteamine. Cystamine underwent a disulfide exchange reaction with the Cys277 residue at the TGM2 active site via a disulfide bond [315]. The newly formed cysteamine–TGM2 complex blocked the natural substrate binding pocket of TGM2 and halted the transacylation step [316]. An in vitro study revealed that cysteamine blocked 5-HT-induced fibronectin serotonylation [154]. Another in vivo study demonstrated that cysteamine abrogated monocrotaline-induced pulmonary arterial hypertension [148]. To date, cysteamine has been the only commercialized TGM2 inhibitor, and its disease indications have been broadened by Raptor Pharmaceuticals. In the future, diseases related to abnormal serotonylation such as chronic lymphocytic leukemia and nephropathic cystinosis may benefit from cysteamine [317].

Another representative reversible TGM2 inhibitor was GK921. GK921 did not bind to the active transglutaminase sites of TGM2. Instead, GK921 bound to the N-terminal (81–116 amino acids (a.a.)) of TGM2 to suppress its transglutaminase activity through accelerating the noncovalent self-assembly of TGM2 polymers [318]. In vitro and in vivo studies showed that GK921 inhibited renal cell carcinoma progression by stabilizing P53 [319]. Moreover, GK921 reversed the pathogenesis of other diseases including glioblastoma, pancreatic cancer, pulmonary fibrosis, and cardiac fibrosis [320–323]. However, no clinical trials have investigated the effects of GK921 in humans.

Conclusions and future directions

In addition to its traditional role as a neurotransmitter in the nervous system, serotonin could also be synthesized and played specific roles in the peripheral system. Serotonin in the extracellular microenvironment was bound to 5-HT receptors and activated downstream signaling cascades or was re-taken up into cells via SERT. Novel posttranslational modification serotonylation, which was catalyzed by TGMs using serotonin re-taken up from SERT as substrates, has been identified for decades. Serotonylation occurred in both histone and nonhistone proteins and was involved in various physiological and pathological processes, making it a promising target for treating related diseases.

Present obstacles for research and “bench to bedside” translation included how to detect serotonylation and how to develop strategies with greater specificity and fewer side effects. First, serotonylated proteins were difficult to purify and visualize [13]. The development of an easier, more direct, and more effective detection method was urgent. In addition, although related drugs such as cysteamine have been used in patients with thrombi or pulmonary arterial hypertension [314], their effects on other pathological conditions were unknown. Recently, chimeric antigen receptor T (CAR-T) cells have been widely used in clinical practice because of their high specificity and proliferation ability in vivo [324]. TPH-1-overexpressed CAR-T cells have been shown to improve antitumor effects [4]. Determining whether CAR-T cells bearing other effectors related to serotonylation could improve clinical effects is a highly anticipated research direction. Finally, given that histone serotonylation often involved crosstalk with other histone modifications such as histaminylation, methylation, and citrullination [30, 33, 121], a combined strategy to target multiple types of histone modifications may yield better effects. Precision matters a lot!

Notably, as serotonylation was a form of monoaminylation, which also involved histaminylation and dopaminylation, several problems need to be solved. First, how do monoaminyl marks interact with other posttranslational modifications such as lactylation and succinylation? Given that the 5-HT signaling cascade through 5-HT receptors was involved in a crosstalk between the gut and the brain [325], the second question is whether monoaminylation dynamics underlie gut–brain axis communication? Third, can isoform-specific TGM2 modulators achieve tissue-selective effects? As detection technologies are evolving, this field promises novel epigenetic therapeutics for complex diseases.

Recently, one study redefined bivalent chromatin as a spatially organized regulatory platform that harnessed transposable elements for gene regulation [326]. The discovery of H3K9me3/H3K27ac bivalency on SINE-VNTR-Alu illustrated how “junk DNA” enabled the precise control of cell fate, transiting from hematopoiesis to aging [326]. Considering that H3Q5 serotonylation and H3Q5 histaminylation often repelled each other [33], whether these two types of histone modifications coexist in DNA and exert dual regulatory effects on gene transcription is unknown. Resolving this question could enrich our knowledge of bivalent chromatin from the perspective of rare posttranslational modifications.

Acknowledgements

The authors show their appreciation for all the members in Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China. Besides, the first author (Jia-Ming Wang) wanted to show sincere appreciation for his best friend Xin-Yue Xu: Thank you for growing up with me, thank you for every kind hospitality and thank you for always being by my side whenever.

Abbreviations

5-HIAA: 5-Hydroxyindolacetic acid
5-HTR: 5-HT receptor
AAAD: Aromatic amino acid decarboxylase
cAMP: Cyclic adenosine monophosphate
CAR-T: Chimeric antigen receptor T
Cdc42: Cell division control protein 42 homolog
CREB: CAMP-response element binding protein
CUT&Tag: Cleavage under targets and tagmentation
DRD4: D(4) dopamine receptor
ETV5: ETS translocation variant 5
GAPDH: Glyceraldehyde-3-phosphate dehydrogenase
H3cit: Histone H3 citrullination
H3K4me3: Histone H3 lysine 4 trimethylation
H3Q5ser: Histone H3 glutamine 5 serotonylation
5-HTR2A: 5-Hydroxytryptamine receptor 2A
KDM5A: Lysine-specific demethylase 5A
KDM5B/C: Lysine-specific demethylase 5B/C
LSD1: Lysine-specific demethylase 1
MAOA: Mitochondrial monoamine oxidase A
MDC: Monodansylcadaverine
MLL1: Histone-lysine N-methyltransferase 2A
mTOR: Mammalian target of rapamycin
MYC: Myc proto-oncogene protein
PD-L1: Programmed cell death 1 ligand 1
PI3K/AKT: Phosphoinositide 3‐kinase/protein kinase B
PKA: Protein kinase A
PKC: Protein kinase C
Rab4: Ras-related protein Rab4
RhoA: Transforming protein RhoA
RIPK3: Receptor-interacting serine/threonine-protein kinase 3
SERCA: Sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase
SERT: Serotonin transporter
SSRIs: Selective serotonin reuptake inhibitors
TAF3: TFIID subunit 3
TCR: T-cell antigen receptor
TGM: Transglutaminase
TPH: Tryptophan hydroxylase
VAMP2: Associated membrane protein 2
VMAT: Vesicular monoamine transporter
WDR5: WD repeat-containing protein 5

Author contributions

H.-Y. Xie, J.-F. Li, and J.-D. Luo were involved in constructing the frame of the manuscript, participated in the revision and supplied the fund for this research. J.-M. Wang, F.-H. Zhang, Y.-R. Chen, and D.-N. Chen wrote, revised the manuscript and prepared all the figures; J.-D. Luo, J.-F. Li, X. Wang, and L.-P. Xie were involved in revision and participated in discussion.

Funding

This research was supported by grants from National Natural Science Foundation of China (82103243, 82372949, 82403161), Zhejiang Provincial Key R&D Program (2023C03073, 2026C02A1162), Zhejiang Province Medical and Health Scientific Research Project (2023RC154), Natural Science Foundation of Zhejiang Province (LMS25H160016, LMS26H160004), Beijing Weikang Public Welfare Foundation (WK2024-003), Medical Education Research Project of The First Affiliated Hospital, College of Medicine, Zhejiang University (zyjg202426).

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jia-Ming Wang, Feng-Hao Zhang, Yi-Ru Chen, Dan-Ni Chen have contribute equally to this work.

Contributor Information

Xiao Wang, Email: zjuwangxiao@zju.edu.cn.

Hai-Yun Xie, Email: 12018518@zju.edu.cn.

Jiang-Feng Li, Email: lijf@zju.edu.cn.

Jin-Dan Luo, Email: luojindan@zju.edu.cn.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Citations

Li H, Wu J, Zhang N, Zheng Q. Transglutaminase 2-mediated histone monoaminylation and its role in cancer. 2024. Biosci Rep. 10.1042/BSR20240493. [DOI] [PMC free article] [PubMed]

Data Availability Statement

No datasets were generated or analyzed during the current study.

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PERMALINK

Beyond neurotransmission: the roles of serotonylation in physiological and pathological processes

Jia-Ming Wang

Feng-Hao Zhang

Yi-Ru Chen

Dan-Ni Chen

Xiao Wang

Hai-Yun Xie

Jiang-Feng Li

Jin-Dan Luo

Li-Ping Xie

Abstract

Introduction

Fig. 1.

Pathways concerning serotonin synthesis and degradation

Fig. 2.

Serotonin receptors and biological functions of the serotonin/serotonin receptor signaling cascade

Table 1.

Central nervous system regulation

Mood and emotional homeostasis

Cognition and memory formation

Sleep–wake regulation

Peripheral system regulation

Gastrointestinal motility

Hemostasis and vascular tone

Metabolic homeostasis

Serotonin signaling through serotonin transporter

Discovery of serotonylation

“Writer,” “reader,” and “eraser” for serotonylation

TGM2 at a glance

Fig. 3.

Fig. 4.

Molecular mechanism behind TGM2-mediated serotonylation

Abundant hypothesis: an update

Methods to detect serotonylation

Direct measurement of serotonin

Radioactive serotonin

Biorthogonal-labeled serotonin

Corresponding antibodies targeting serotonylated proteins

Two-dimensional gel electrophoresis

Competitive mechanism

Mass spectrometry

Regioselective rapid ene-type reaction

Chemoselective rapid azo-coupling reaction

Cleavage under targets and tagmentation

Single-cell mono-aminylomics

Known targets for serotonylation

Fig. 5.

Table 2.

Histone

Fig. 6.

Cytoskeletal proteins

Fibronectin

Small GTPases

Other proteins

Summary

Relationship between serotonin receptor-mediated signaling and SERT-mediated serotonylation

Strategies to target serotonylation

Fig. 7.

Table 3.

Blocking serotonin synthesis

Blocking SERT

Blocking TGM2

Conclusions and future directions

Acknowledgements

Abbreviations

Author contributions

Funding

Data availability

Declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Footnotes

Contributor Information

References

Associated Data

Data Citations

Data Availability Statement

ACTIONS