Abstract
After the initial discovery of intermediate filament (IF)-forming proteins in 1968, a decade would elapse before they were revealed to comprise a diverse group of proteins which undergo tissue-, developmental stage-, differentiation- and context-dependent regulation. Our appreciation for just how large (n=70), conserved, complex, and dynamic IF genes and proteins are became even sharper upon completion of the human genome project. While there has been extraordinary progress in understanding the multimodal roles of IFs in cells and tissues, even revealing them as direct causative agents in a broad array of human genetic disorders, the link between individual IFs and cell differentiation has remained elusive. Here we review evidence that demonstrates a role for IFs in lineage determination, cell differentiation, and tissue homeostasis. A major theme in this review is the function of IFs as sensors and transducers of mechanical forces, intersecting microenvironmental cues and fundamental processes through cellular redox balance.
Keywords: Intermediate filament, keratin, nuclear lamins, differentiation, cell determination, Notch, Hippo, mechanosensing, mechanotransduction, extracellular matrix, redox, disulfides
Introduction
In metazoan genomes, the intermediate filament (IF) super family likely represents the largest group of genes undergoing regulation in clear relation to cell type and differentiation state, particularly in the adult setting. The filament-forming proteins encoded by IF genes play key roles in all major cellular processes including growth and proliferation, migration, response to stress, and death. The direct roles of IF proteins during cell differentiation, however, have puzzlingly remained elusive. At long last, recent studies have uncovered a functional link between select IF proteins and pathways directly impacting cell lineage choices and cell differentiation, including the Notch and Hippo signaling pathways. Key to exposing this connection and actualizing their pro-differentiation influence was the recognition that IF proteins integrate mechanical and biochemical cues through specific, dynamic, and context-dependent post-translational modifications.
This text focuses on lamins, vimentin, nestin and various keratin proteins and their roles toward regulating cell lineage determination and cell differentiation in vivo. The reader is referred to other excellent reviews for an account of progress recently made in understanding other aspects of the properties and physiological roles of IFs [1,2], including their intimate relationship to desmosomes [3,4] and roles in cell migration [5–8] and cancer [9]. Moreover, contributions by Bomont [10] and Eldirany et al. [11] to the current issue of COCB are also focused on IFs.
Lamins, Mechanotransduction, and Cell Fate Specification
The evolution and diversification of the IF superfamily likely originates with nucleoskeletal proteins related to modern day lamins [12]. Through protein-protein interactions with other nuclear lamina and nucleoplasmic proteins and with the cytoskeleton, lamins are critical integrators of nuclear architecture and nuclear mechanics, genome organization, and gene regulation. In mammals, the nuclear lamin network is comprised of three mature lamin proteins: lamin A, B, and C. Lamins A and C are both encoded by the gene LMNA, whose transcript is differentially spliced to yield lamin C or prelamin A, which is further post-translationally processed to yield mature lamin A. Common to lamins A, B, and C is a large, carboxyl-terminal unstructured region which mediates interactions between lamin filaments, nuclear transcription factors and trans-nuclear envelope LINC (Linker of Nucleoskeleton and Cytoskeleton) complexes. The C-terminus of lamin B and prelamin A also contain a CAAX (cysteine-aliphatic-aliphatic-any amino acid) peptide to which a hydrophobic farnesyl group is covalently added, targeting lamin B and prelamin A to the inner nuclear bilayer lipid membrane [13]. Further processing of prelamin A cleaves upstream of its farnesylation site, releasing mature lamin A from the nuclear envelope.
The release of mature lamin A from the nuclear is a crucial step in the proper formation of the lamin A network. Recent biophysical analyses revealed that the oligomerization of lamin A dimer into a staggered head-to-tail conformation allows for the sliding, compression, and stretching of homodimers (within themselves, and in and out of register) [14]. Accordingly, lamin A polymers function as a molecular “spring” whose conformation dynamically relocalizes lamin A-interacting proteins in response to mechanical force on the cell and the nucleus, instructing chromatin conformation and gene regulation ([14]; see [15] for a recent review on lamin structure in situ). Mutations that impair the ability of lamin A to polymerize properly, including mutations in the unstructured, trans-interacting head and tail domains, and mutations that impair the ability of the farnesyl group of prelamin A to be released, are causative for a family of diseases known as laminopathies, whose devastating symptoms include premature aging (Hutchinson–Gilford progeria syndrome) and atherosclerosis [16,17].
While lamins B1/2 are primarily expressed during embryogenesis, lamins A/C are associated with adult tissue homeostasis and differentiation [13]. Consistent with its mechanosensitive “spring” structure, foundational studies within the last decade have revealed lamin A accumulation in the nuclear lamina to be directly correlated with extracellular matrix stiffness [18]. Mesenchymal stem cell (MSC) differentiation provides a vibrant example of the matrix stiffness sensing role of lamin A. In response to increasing matrix stiffness, indeed, lamin A accumulates at the nuclear lamina and shunts MSCs towards osteoblast differentiation. Conversely, reduced matrix stiffness reduces lamin A accumulation, promotes MSC migration and shunts MSCs towards adipocyte differentiation [19,20]. A complex network of pathways underlie this differentiation switch, including retinoic acid signaling, the Hippo pathway via YAP1, and, most recently demonstrated, mesenchymal transcription factors RUNX2/PPAR via the pro-migratory growth factor VEGF [20]. Consistent throughout commitment to MSC differentiation is the role of the lamin A network as a flexible physical scaffold stabilizing the nucleus, preventing cytoplasmic accumulation of various transcription factors, and resisting deformation in response to changes in cell shape due to matrix composition and cell migration.
The relationship between the nucleoskeleton and the cytoskeleton is mediated through trans-nuclear envelope LINC complexes. An extensive body of work has painted a compelling portrait of the highly mechanosensitive nature of the LINC complex and its constituent KASH and SUN domain-containing components. KASH domain-containing proteins bind to the cytoskeleton and pass through the outer nuclear envelope into the perinuclear space where they interact with SUN domain-containing proteins integral to the inner nuclear envelope [21]. Foundational studies on the structure of the LINC complex have shown SUN domain containing proteins SUN1 and SUN2 to bind to the lamin A network [22,23]. The mechanosensitivity of the lamin A network is then transmitted through the nuclear envelope to the cytoskeleton via the interaction of SUN1/2 and NESPRIN1/2. Remarkably, this interaction is dependent on a mechanoresistant disulfide bond between cysteine residue 563 of SUN2 and cysteine residue 6862 of the KASH domain of NESPRIN2 [24]. A recent study has further shown that NESPRINs themselves are mechanosensory, additionally to their coupling with the lamin A network. The tensile nature of NESPRIN was shown to regulate ɑ-catenin nuclear translocation, thereby modulating β-catenin signaling and the epithelial to mesenchymal transition gene program [25].
Vimentin, Redox Regulation, and Cellular Stress
Vimentin is a cytoskeletal IF protein that is prominently expressed during embryonic development but maintained primarily in fibroblasts, leukocytes, and endothelial cells in the adult setting [26]. The vimentin IF network interacts with and provides scaffolding for a diverse set of proteins and cellular processes, including lysosome and aggresome positioning, paracrine and autocrine signaling, and cell migration. A feature of vimentin critical to its diverse functions within a cell is its ability to sense and respond to cellular stress, including oxidative stress [27]. Hypoxia, starvation, high concentrations of ionic calcium, or treatment with oxidative chemicals can result in oxidative stress, which can in turn modify and damage proteins, organelles, and DNA. Oxidative stress can impart post-translational modifications on vimentin filaments, disrupting interactions between charged amino acids exposed on the surface of vimentin filaments and ionic species within the cytoplasm.
Recent work using fluorescently tagged vimentin has revealed the sensitivity of the vimentin filament network to oxidative chemicals, which induce filament disassembly and aggregation [28]. The sensitivity of vimentin filaments to oxidation is mediated through a cysteine residue at position 328 (C328). Remarkably, rather than participating in a disulfide bond, vimentin C328 confers stability to vimentin filaments through coordination with a zinc ion. Oxidative chemicals and mitochondrial reactive oxygen species can non-enzymatically promote addition of a glutathione group at cysteine 328, preventing coordination with zinc and inducing filament disassembly and aggregation. Mutations at cysteine residue 328 protect the vimentin filament network from oxidative stress but impair normal lysosome and aggresome positioning [28]. Dynamic assembly and disassembly of the vimentin filament network is essential to the dramatic changes in cellular morphology required during cell migration [29]. While recent work has demonstrated the key roles of zinc coordination and lipoxidation to vimentin filament assembly and aggregation [28,30], covalent attachment of SUMO protein (SUMOylation) has also been shown to promote dynamic vimentin restructuring in response to cell migration. In turn, loss of PIAS1, an E3 SUMO ligase shown to act on vimentin, impairs migratory ability in the context of HeLa cells [29].
A 2016 study by Cheng et al. [31] provided evidence that vimentin orchestrates the healing of wounds in mouse skin by controlling fibroblast proliferation, TGF-β1-Slug signaling, collagen accumulation, and epithelial-mesenchymal transition, with an associated impact on the keratinocyte differentiated state in the wound epithelium. Such findings add to the notion that (see below) IFs can impact cell differentiation pathways in a “paracrine”, non-cell autonomous fashion.
Keratins, Epithelial Differentiation and Homeostasis, and Hippo Signaling
Keratin IFs are an extensive gene family (N=54) whose expression is tightly regulated in response to epithelial specification and differentiation status [32]. The role of keratin proteins in epithelial mechanical integrity and the role that keratin mutations play in disease have been explored and expanded upon for the last three decades [33–35]. Until recently, however, the extensive body of work detailing the unique and essential role for the keratin IF network in the mechanical barrier function of epithelia had not yet implicated a direct role for keratin proteins in epithelial homeostasis.
Keratin 14 (K14) represents the main type I keratin protein expressed in the basal, progenitor compartment of stratified squamous epithelia in organs such as the skin and oral mucosa. As basal keratinocytes exit the progenitor compartment upon commitment to terminal differentiation, expression of K14 is turned off, and expression of the differentiation-marking type I keratin 10 (K10) is turned on [36]. A recent study in mice has elucidated a direct role for K14 in the maintenance of epithelial homeostasis in the context of the skin, achieved via interaction with the scaffolding protein 14-3-3σ (stratifin) and the Hippo pathway transcriptional coactivator YAP1. In a K14 disulfide bond-dependent manner involving cysteine residue 373 (367 in human K14), K14 binds 14-3-3σ and in turn retains YAP1 in the cytoplasm upon entry into terminal differentiation (Figure 1). Loss of cysteine residue 373, located in the K14 coiled-coil stutter, attenuates K14 disulfide bonding, resulting in 14-3-3σ aggregation, abnormal YAP1 nuclear localization in the suprabasal compartment and impaired terminal differentiation [37].
Figure 1.
The intermediate filament apparatus as a novel regulator and YAP1/Hippo signaling in the interfollicular epidermis. Two general types of basal keratinocytes, differentiation-committed (yellow) and proliferating, stem-like (pink), are attached to the extracellular matrix (ECM) via ɑ6β4 integrin-containing hemidesmosomes. Recent studies revealed that K5-K14 filaments [37] and hemidesmosomes [42] partake in regulating the localization and function of YAP1, a terminal (transcriptional) effector of Hippo signaling, with an associated impact on keratinocyte differentiation and epidermal homeostasis. Guo et al. [37] provided evidence that initiation of terminal differentiation in late stage progenitor keratinocytes in the basal layer entails the formation of K14-dependent disulfides via the conserved stutter cysteine in coil 2 domain, concomitant with a reorganization of keratin filaments around the nucleus, recruitment of 14-3-3σ onto keratin filaments and, as a result, sequestration of YAP1 in the cytoplasm and activation of Hippo signaling. Guo et al. proposed an identical role for the conserved cysteine in coil 2 of keratin 10, which is expressed early during terminal differentiation, thereby maintaining YAP1’s sequestration to the cytoplasm and active Hippo signaling. Wang et al. [42] showed that integrin α6β4 regulates YAP1 activity through the inhibition of Rho-ROCK-MLC- and FAK-PI3K- dependent signaling pathways. How these events reflect the integration of mechanical cues as early differentiating keratinocytes lose contact with the ECM via delamination and upregulate cell-cell adhesion via desmosomes and adherens junction, warrants further investigation. On another front, the schematic conveys that K6a/K6b/K16 filaments, which occurs under stress conditions in the epidermis and in specific body sites of the skin interacts with mitochondria (cyan) through a yet to be determined mechanism, keratins 6a/b and 16 are expressed (gray).
The stutter motif, a disruption in the coiled-coil forming heptad repeating sequence of K14 with its constituent cysteine residue, is a conserved feature of closely related type I keratins, including K10, K16, and K17 [37,38]. Both K14 and K10 have been shown to participate in homotypic disulfide bonds mediated by their stutter motif cysteine residues [37–39]. While only K14 has so far been shown to participate in the regulation of YAP1 localization and Hippo signaling in epithelia, the intriguing conservation of the contributing stutter motif between type I keratins occupying distinct epithelial niches offers exciting speculation to the fundamental nature of this stutter motif in regulation of epithelial homeostasis via the Hippo pathway (Figure 1).
The link between keratin, YAP1 regulation, and Hippo signaling may further extend beyond the stutter cysteine. Indeed, a recent study has shown that K8-K18 filaments are asymmetrically partitioned in early stage, pre-implantation human and mouse embryos. This asymmetric partitioning was shown to be instrumental to the polarization and formation of the trophectoderm (extra-embryonic tissue) through a yet-to-be-defined mechanism that entails aPKC signaling, YAP1 induction, and homeobox protein CDX2 [40]. Yet another finding of note in this study is that interactions between F-actin and K8-K18 filaments are key to achieving trophectoderm lineage determination [40]. Like K14 and many other IF proteins, K18 can bind 14-3-3 in a phosphorylation-dependent fashion [41], though K18 does not feature the stutter cysteine [38], raising the issue of the precise mechanism linking keratin to YAP regulation in pre-implantation stage embryos.
The intersection between keratin IFs and epithelial differentiation and homeostasis is likely multimodal, encompassing numerous mechanosensitive and energetic facets of cell biology. The homeostasis-impairing loss of K14 cysteine residue 373 has been demonstrated to act through the mechanosensitive effector YAP1, with a marked impact on nuclear lamina composition and cadherin cell-cell junctions [37]. The integrin α6β4 complex, a component of hemidesmosomes which mediate the attachment of the cytoplasmic facing K5-K14 filament network to the extracellular matrix of keratinocytes, acts as a mechanotransducer by regulating the activity of YAP1 through inhibition of the Rho-ROCK-MLC- and FAK-PI3K-dependent signaling pathways [42]. In another study [43], the absence of K16 was found to result in a striking differentiation defect in the force-bearing mouse footpad epidermis, ahead of the development of palmoplantar keratoderma-like lesions. In this particular instance, the signaling pathway(s) underlying the defect have not been identified, though the high mechanical stress endured by the mouse footpad leads to intriguing speculation.
Further, mitochondrial dynamics are altered in skin keratinocytes lacking either K6a/K6b or K16 [44] (Figure 1). Loss of keratin 6a (K6a), a type II keratin expressed in palmoplantar skin and nail beds, has been shown to alter mitochondrial dynamics, impair mitophagy, ultimately resulting in increased cytoplasmic reactive oxygen species (ROS) [45]. Similarly, loss of K8 in insulin-secreting β cells induces mitochondrial fragmentation, culminating in impaired ATP and insulin production [46]. Relatedly, a recent study focusing on desmin IFs showed that various mutant forms associated with skeletal myopathies disrupt mitochondrial architecture, dynamics and function irrespective or their potential to form insoluble aggregates in skeletal muscle cells [47]. Evidence supporting a dynamic interplay between various types of IFs, mitochondria, and mitochondria-dependent processes is rapidly growing, in fact, as conveyed in recent review articles [6,48]. We envision that the IF-mitochondria partnership in addition to the mechanosensitive nature of IF networks and their intersecting pathways is critical to the maintenance of optimal cellular functioning as part of the differentiated state.
Intermediate Filaments as Regulators of Notch Signaling
As the predominant cytoplasmic IF in mesenchymal cells, the vimentin filament network has been shown to be critical to the mechanical integrity of fibroblasts experiencing cellular deformation [49]. The unique elasticity and turnover properties of the vimentin filament network allows mesenchyme-derived cells to both resist and effectively absorb mechanical forces they may experience during organ development, cell migration, and wounding. The function of the vimentin filament network as an elastic “shock absorber” for shear stress has recently been demonstrated to affect endothelial cell transcription and homeostasis through the Notch signaling pathway [50] (Figure 2a). In addition to being able to stretch significantly without breakage or disassembly, vimentin has been shown to be phosphorylated at serine residue 38 in response to the mechanical stress exerted on blood vessels. This stress-dependent posttranslational modification promotes the interaction between vimentin and the cell surface ligand Jagged1, enhancing its cooperation with Notch and the downstream Notch signaling pathway gene program in endothelial cells [50].
Figure 2.
Intersections of intermediate filaments and the Notch signaling pathway
a. Cross section of an endothelium. Endothelial cells lining the interior of blood vessels experience significant shear forces from the pumping of blood. The ability of endothelial cells to sense and respond to these shear forces is in part afforded through the spring-like action of the vimentin filament network (orange). In response to mechanical stress, vimentin is site-specifically phosphorylated, promoting its interaction with the surface ligand JAG1 (purple) and subsequent Notch (green) activation [50].
b. Cross section of a representational simple epithelium. In the context of gut simple epithelia, enterocytes express keratins 8/18/19 (red). These keratin networks interact with the intracellular domain of Notch (green). Interactions between K8 and Notch effect Notch protein levels and subsequent levels and transcriptional activity of the Notch effector NICD (green), balancing simple epithelial differentiation between enterocyte and mucus-producing goblet cell (pink) [51]. In heterogenous contexts, intermediate filaments (peach) have been shown to impact the internalization of JAG1 endosomes and subsequent Notch activity in neuronal stem cells which express nestin intermediate filaments [53], as well as interact and effect the fitness of mitochondria (cyan) in pancreatic beta cells which express K8/K18 [46].
A role for keratins in the Notch signaling pathway has also recently been described. Keratins 8/18/19, expressed primarily in simple epithelia particularly in the gut, have been shown to interact with Notch1 and promote expression of the downstream Notch gene program and promote colonic epithelial homeostasis [51] (Figure 2b). Loss of K8 by CRISPRCas9 knockout reduces Notch1 proteins levels and subsequent expression of Notch1 target genes, culminating in a shift in differentiation status from a balanced, simple epithelium to a hyperproliferative, secretory cell-like state [51]. There is evidence linking K14 to the Notch signaling pathway in the oral mucosa via a master regulator of epithelial identity and differentiation, p63 [52]. Intriguingly, epidermis harboring a cysteine to alanine mutation at K14 stutter residue 373 displays an overall reduction in nuclear p63 staining and marked reduction in nuclear p63 staining basal keratinocytes [37].
Finally, the regulation of neuronal stem cell differentiation has recently been shown to be impacted by the type VI IF nestin. Nestin is a unique IF with a large, unstructured carboxy terminal tail expressed in the mammalian nervous system [26]. A recent study examining 3D cultures of neural progenitor cells derived from nestin-knockout mice revealed nestin to be antagonistic to neuronal differentiation in an astrocyte-dependent manner. Nestin was shown to promote the activation of Notch signaling in extraneuronal, supportive astrocytes, thereby inhibiting differentiation in associated neuronal stem cells, by appropriately partitioning vesicles containing endocytosed surface ligands, Jag1 [53].
Concluding remarks
After decades of groundbreaking research on IF biology, a substantive link between IF proteins and the regulation of cell differentiation has at last been revealed in multiple tissue and organ settings. Multiple factors may account for the delay in exposing a reality that has seemed intuitively so obvious to many – foremost, the need for in vivo investigations in the natural setting of organs and tissues to discover the intersection of dynamically-regulated posttranslational modifications of IFs and multimodal signaling inputs, including mechanical cues. While recent progress has been inspirational, many questions remain, spearheading yet another new beginning in the fascinating sphere of IF research [54].
Acknowledgments
The authors are grateful to members of the laboratory for support, to Drs. M. Bishr Omary and Diana Toivola for advice, and to grants R01/R56AR047042 and R01AR044232 (to PAC) and T32 CA009696 (to CJR) for support.
Footnotes
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