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Special Issue "Recent Advances in Intermediate Filaments"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 31 May 2021.

Special Issue Editor

Dr. Jose Maria Gonzalez-Granado
Website
Guest Editor
LamImSys Lab. Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain
Interests: lamin A/C; T cell; dendritic cell; inflammatory bowel disease; melanoma; pathogen infections; immunology

Special Issue Information

Dear Colleagues,

Intermediate filaments (IFs) are part of the cellular cytoskeleton and nucleoskeleton. They participate in the connection between the cell membrane and the nuclear interior with actin filaments, microtubules, and the linker of nucleoskeleton and cytoskeleton (LINC) complex. IFs are responsible for the critical structural integrity of cells and tissues and regulate several important cellular processes including cell migration and adhesion, apoptosis, proliferation, differentiation, autophagy, signaling, gene expression, vesicle trafficking, mitochondrial function, and cell fate determination. Although IFs are expressed in most cells, their expression is dynamic and subject to fine regulation involving post-translational modifications and intracellular proteolysis. Mutation in IF genes results in a wide range of human diseases; these filaments play important roles in the context of cancer, inflammation and other immune diseases, muscular syndromes, progeria, lipodystrophies, and digestive diseases.In this Special Issue, we invite investigators to submit original research or review articles on the many facets of intermediate filament and on recent insights in this field.Topics include but are not limited to the following: 

  • IF and mechanobiology
  • IF modifications and regulation
  • IF in nuclear function
  • IF in signaling
  • IF in digestive biology and diseases.
  • IF in immunology and inflammation
  • IF in cancer
  • IF in laminopathies
  • IF in muscular diseases

Dr. Jose Maria Gonzalez-Granado
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • intermediate filaments
  • lamins
  • keratins
  • vimentin
  • nestin
  • mechanics
  • migration
  • signaling
  • transcription
  • vesicle trafficking
  • mitochondrial function
  • inflammation
  • cancer
  • digestive diseases

Published Papers (11 papers)

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Research

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Open AccessArticle
Hemidesmosome-Related Keratin Filament Bundling and Nucleation
Int. J. Mol. Sci. 2021, 22(4), 2130; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042130 - 21 Feb 2021
Abstract
The epithelial cytoskeleton encompasses actin filaments, microtubules, and keratin intermediate filaments. They are interconnected and attached to the extracellular matrix via focal adhesions and hemidesmosomes. To study their interplay, we inhibited actin and tubulin polymerization in the human keratinocyte cell line HaCaT by [...] Read more.
The epithelial cytoskeleton encompasses actin filaments, microtubules, and keratin intermediate filaments. They are interconnected and attached to the extracellular matrix via focal adhesions and hemidesmosomes. To study their interplay, we inhibited actin and tubulin polymerization in the human keratinocyte cell line HaCaT by latrunculin B and nocodazole, respectively. Using immunocytochemistry and time-lapse imaging of living cells, we found that inhibition of actin and tubulin polymerization alone or in combination induced keratin network re-organization albeit differently in each situation. Keratin filament network retraction towards the nucleus and formation of bundled and radial keratin filaments was most pronounced in latrunculin-B treated cells but less in doubly-treated cells and not detectable in the presence of nocodazole alone. Hemidesmosomal keratin filament anchorage was maintained in each instance, whereas focal adhesions were disassembled in the absence of actin filaments. Simultaneous inhibition of actin and tubulin polymerization, therefore, allowed us to dissect hemidesmosome-specific functions for keratin network properties. These included not only anchorage of keratin filament bundles but also nucleation of keratin filaments, which was also observed in migrating cells. The findings highlight the fundamental role of hemidesmosomal adhesion for keratin network formation and organization independent of other cytoskeletal filaments pointing to a unique mechanobiological function. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Open AccessArticle
Identification of a Novel Link between the Intermediate Filament Organizer IFO-1 and Cholesterol Metabolism in the Caenorhabditis elegans Intestine
Int. J. Mol. Sci. 2020, 21(21), 8219; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218219 - 03 Nov 2020
Abstract
The intestine is an organ essential to organismal nutrient absorption, metabolic control, barrier function and immunoprotection. The Caenorhabditis elegans intestine consists of 20 cells harboring a dense intermediate filament network positioned below the apical plasma membrane that forms a junction-anchored sheath around the [...] Read more.
The intestine is an organ essential to organismal nutrient absorption, metabolic control, barrier function and immunoprotection. The Caenorhabditis elegans intestine consists of 20 cells harboring a dense intermediate filament network positioned below the apical plasma membrane that forms a junction-anchored sheath around the intestinal lumen. This evolutionarily conserved arrangement provides mechanical and overall stress-protection, and it serves as an important model for deciphering the role of intestinal architecture in metazoan biology. We recently reported that the loss-of-function mutation of the intestinal intermediate filament organizer IFO-1 perturbs this architecture, leading to reduced body size and reproduction. Here, we demonstrate that the IFO-1 mutation dramatically affects cholesterol metabolism. Mutants showed an increased sensitivity to cholesterol depletion, reduced cholesterol uptake, and cholesterol transfer to the gonads, which is also observed in worms completely lacking an intermediate filament network. Accordingly, we found striking similarities to transcriptome and lipidome profiles of a nuclear hormone receptor (NHR)-8 mutant. NHR-8 is homologous to mammalian LXR (liver X receptor) that serves as a sterol sensor and transcriptional regulator of lipid metabolism. Remarkably, increasing exogenous cholesterol partially rescues the developmental retardation in IFO-1 mutants. Our results uncover a novel link of the intestinal intermediate filament cytoskeleton to cholesterol metabolism that contributes to compromised growth and reproduction. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Open AccessArticle
Desmin Interacts Directly with Mitochondria
Int. J. Mol. Sci. 2020, 21(21), 8122; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218122 - 30 Oct 2020
Abstract
Desmin intermediate filaments (IFs) play an important role in maintaining the structural and functional integrity of muscle cells. They connect contractile myofibrils to plasma membrane, nuclei, and mitochondria. Disturbance of their network due to desmin mutations or deficiency leads to an infringement of [...] Read more.
Desmin intermediate filaments (IFs) play an important role in maintaining the structural and functional integrity of muscle cells. They connect contractile myofibrils to plasma membrane, nuclei, and mitochondria. Disturbance of their network due to desmin mutations or deficiency leads to an infringement of myofibril organization and to a deterioration of mitochondrial distribution, morphology, and functions. The nature of the interaction of desmin IFs with mitochondria is not clear. To elucidate the possibility that desmin can directly bind to mitochondria, we have undertaken the study of their interaction in vitro. Using desmin mutant Des(Y122L) that forms unit-length filaments (ULFs) but is incapable of forming long filaments and, therefore, could be effectively separated from mitochondria by centrifugation through sucrose gradient, we probed the interaction of recombinant human desmin with mitochondria isolated from rat liver. Our data show that desmin can directly bind to mitochondria, and this binding depends on its N-terminal domain. We have found that mitochondrial cysteine protease can disrupt this interaction by cleavage of desmin at its N-terminus. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Open AccessArticle
Unidirectional Regulation of Vimentin Intermediate Filaments to Caveolin-1
Int. J. Mol. Sci. 2020, 21(20), 7436; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207436 - 09 Oct 2020
Cited by 1
Abstract
Both the mechanosensitive vimentin cytoskeleton and endocytic caveolae contribute to various active processes such as cell migration, morphogenesis, and stress response. However, the crosstalk between these two systems has remained elusive. Here, we find that the subcellular expression between vimentin and caveolin-1 is [...] Read more.
Both the mechanosensitive vimentin cytoskeleton and endocytic caveolae contribute to various active processes such as cell migration, morphogenesis, and stress response. However, the crosstalk between these two systems has remained elusive. Here, we find that the subcellular expression between vimentin and caveolin-1 is mutual exclusive, and vimentin filaments physically arrest the cytoplasmic motility of caveolin-1 vesicles. Importantly, vimentin depletion increases the phosphorylation of caveolin-1 on site Tyr14, and restores the compromised cell migration rate and directionality caused by caveolin-1 deprivation. Moreover, upon hypo-osmotic shock, vimentin-knockout recovers the reduced intracellular motility of caveolin-1 vesicles. In contrary, caveolin-1 depletion shows no effect on the expression, phosphorylation (on sites Ser39, Ser56, and Ser83), distribution, solubility, and cellular dynamics of vimentin filaments. Taken together, our data reveals a unidirectional regulation of vimentin to caveolin-1, at least on the cellular level. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Open AccessArticle
c-Abl Tyrosine Kinase Is Regulated Downstream of the Cytoskeletal Protein Synemin in Head and Neck Squamous Cell Carcinoma Radioresistance and DNA Repair
Int. J. Mol. Sci. 2020, 21(19), 7277; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197277 - 01 Oct 2020
Abstract
The intermediate filament synemin has been previously identified as novel regulator of cancer cell therapy resistance and DNA double strand break (DSB) repair. c-Abl tyrosine kinase is involved in both of these processes. Using PamGene technology, we performed a broad-spectrum kinase activity profiling [...] Read more.
The intermediate filament synemin has been previously identified as novel regulator of cancer cell therapy resistance and DNA double strand break (DSB) repair. c-Abl tyrosine kinase is involved in both of these processes. Using PamGene technology, we performed a broad-spectrum kinase activity profiling in three-dimensionally, extracellular matrix grown head and neck cancer cell cultures. Upon synemin silencing, we identified 86 deactivated tyrosine kinases, including c-Abl, in irradiated HNSCC cells. Upon irradiation and synemin inhibition, c-Abl hyperphosphorylation on tyrosine (Y) 412 and threonine (T) 735 was significantly reduced, prompting us to hypothesize that c-Abl tyrosine kinase is an important signaling component of the synemin-mediated radioresistance pathway. Simultaneous targeting of synemin and c-Abl resulted in similar radiosensitization and DSB repair compared with single synemin depletion, suggesting synemin as an upstream regulator of c-Abl. Immunoprecipitation assays revealed a protein complex formation between synemin and c-Abl pre- and post-irradiation. Upon pharmacological inhibition of ATM, synemin/c-Abl protein-protein interactions were disrupted implying synemin function to depend on ATM kinase activity. Moreover, deletion of the SH2 domain of c-Abl demonstrated a decrease in interaction, indicating the dependency of the protein-protein interaction on this domain. Mechanistically, radiosensitization upon synemin knockdown seems to be associated with an impairment of DNA repair via regulation of non-homologous end joining independent of c-Abl function. Our data generated in more physiological 3D cancer cell culture models suggest c-Abl as further key determinant of radioresistance downstream of synemin. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Open AccessArticle
Withaferin-A Can Be Used to Modulate the Keratin Network of Intermediate Filaments in Human Epidermal Keratinocytes
Int. J. Mol. Sci. 2020, 21(12), 4450; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124450 - 23 Jun 2020
Abstract
The mechanical state of cells is a critical part of their healthy functioning and it is controlled primarily by cytoskeletal networks (actin, microtubules and intermediate filaments). Drug-based strategies targeting the assembly of a given cytoskeletal network are often used to pinpoint their role [...] Read more.
The mechanical state of cells is a critical part of their healthy functioning and it is controlled primarily by cytoskeletal networks (actin, microtubules and intermediate filaments). Drug-based strategies targeting the assembly of a given cytoskeletal network are often used to pinpoint their role in cellular function. Unlike actin and microtubules, there has been limited interest in the role of intermediate filaments, and fewer drugs have thus been identified and characterised as modulators of its assembly. Here, we evaluate whether Withaferin-A (WFA), an established disruptor of vimentin filaments, can also be used to modulate keratin filament assembly. Our results show that in keratinocytes, which are keratin-rich but vimentin-absent, Withaferin-A disrupts keratin filaments. Importantly, the dosages required are similar to those previously reported to disrupt vimentin in other cell types. Furthermore, Withaferin-A-induced keratin disassembly is accompanied by changes in cell stiffness and migration. Therefore, we propose that WFA can be repurposed as a useful drug to disrupt the keratin cytoskeleton in epithelial cells. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Open AccessArticle
Stable Fibroblast Growth Factor 2 Dimers with High Pro-Survival and Mitogenic Potential
Int. J. Mol. Sci. 2020, 21(11), 4108; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114108 - 09 Jun 2020
Abstract
Fibroblast growth factor 2 (FGF2) is a heparin-binding growth factor with broad mitogenic and cell survival activities. Its effector functions are induced upon the formation of 2:2 FGF2:FGFR1 tetrameric complex. To facilitate receptor activation, and therefore, to improve the FGF2 biological properties, we [...] Read more.
Fibroblast growth factor 2 (FGF2) is a heparin-binding growth factor with broad mitogenic and cell survival activities. Its effector functions are induced upon the formation of 2:2 FGF2:FGFR1 tetrameric complex. To facilitate receptor activation, and therefore, to improve the FGF2 biological properties, we preorganized dimeric ligand by a covalent linkage of two FGF2 molecules. Mutations of the FGF2 WT protein were designed to obtain variants with a single surface-exposed reactive cysteine for the chemical conjugation via maleimide-thiol reaction with bis-functionalized linear PEG linkers. We developed eight FGF2 dimers of defined topology, differing in mutual orientation of individual FGF2 molecules. The engineered proteins remained functional in terms of FGFR downstream signaling activation and were characterized by the increased stability, mitogenic potential and anti-apoptotic activity, as well as induced greater migration responses in normal fibroblasts, as compared to FGF2 monomer. Importantly, biological activity of the dimers was much less dependent on the external heparin administration. Moreover, some dimeric FGF2 variants internalized more efficiently into FGFR overexpressing cancer cells. In summary, in the current work, we showed that preorganization of dimeric FGF2 ligand increased the stability of the growth factor, and therefore, enhanced its biological activity. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Open AccessArticle
Zinc Differentially Modulates the Assembly of Soluble and Polymerized Vimentin
Int. J. Mol. Sci. 2020, 21(7), 2426; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072426 - 31 Mar 2020
Cited by 5
Abstract
The intermediate filament protein vimentin constitutes a critical sensor for electrophilic and oxidative stress. We previously showed that vimentin interacts with zinc, which affects its assembly and redox sensing. Here, we used vimentin wt and C328S, an oxidation-resistant mutant showing improved NaCl-induced polymerization, [...] Read more.
The intermediate filament protein vimentin constitutes a critical sensor for electrophilic and oxidative stress. We previously showed that vimentin interacts with zinc, which affects its assembly and redox sensing. Here, we used vimentin wt and C328S, an oxidation-resistant mutant showing improved NaCl-induced polymerization, to assess the impact of zinc on soluble and polymerized vimentin by light scattering and electron microscopy. Zinc acts as a switch, reversibly inducing the formation of vimentin oligomeric species. High zinc concentrations elicit optically-detectable vimentin structures with a characteristic morphology depending on the support. These effects also occur in vimentin C328S, but are not mimicked by magnesium. Treatment of vimentin with micromolar ZnCl2 induces fibril-like particles that do not assemble into filaments, but form aggregates upon subsequent addition of NaCl. In contrast, when added to NaCl-polymerized vimentin, zinc increases the diameter or induces lateral association of vimentin wt filaments. Remarkably, these effects are absent or attenuated in vimentin C328S filaments. Therefore, the zinc-vimentin interaction depends on the chemical environment and on the assembly state of the protein, leading to atypical polymerization of soluble vimentin, likely through electrostatic interactions, or to broadening and lateral association of preformed filaments through mechanisms requiring the cysteine residue. Thus, the impact of zinc on vimentin assembly and redox regulation is envisaged. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Review

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Open AccessReview
Deimination, Intermediate Filaments and Associated Proteins
Int. J. Mol. Sci. 2020, 21(22), 8746; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228746 - 19 Nov 2020
Abstract
Deimination (or citrullination) is a post-translational modification catalyzed by a calcium-dependent enzyme family of five peptidylarginine deiminases (PADs). Deimination is involved in physiological processes (cell differentiation, embryogenesis, innate and adaptive immunity, etc.) and in autoimmune diseases (rheumatoid arthritis, multiple sclerosis and lupus), cancers [...] Read more.
Deimination (or citrullination) is a post-translational modification catalyzed by a calcium-dependent enzyme family of five peptidylarginine deiminases (PADs). Deimination is involved in physiological processes (cell differentiation, embryogenesis, innate and adaptive immunity, etc.) and in autoimmune diseases (rheumatoid arthritis, multiple sclerosis and lupus), cancers and neurodegenerative diseases. Intermediate filaments (IF) and associated proteins (IFAP) are major substrates of PADs. Here, we focus on the effects of deimination on the polymerization and solubility properties of IF proteins and on the proteolysis and cross-linking of IFAP, to finally expose some features of interest and some limitations of citrullinomes. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Open AccessReview
Lamin A/C and the Immune System: One Intermediate Filament, Many Faces
Int. J. Mol. Sci. 2020, 21(17), 6109; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176109 - 25 Aug 2020
Abstract
Nuclear envelope lamin A/C proteins are a major component of the mammalian nuclear lamina, a dense fibrous protein meshwork located in the nuclear interior. Lamin A/C proteins regulate nuclear mechanics and structure and control cellular signaling, gene transcription, epigenetic regulation, cell cycle progression, [...] Read more.
Nuclear envelope lamin A/C proteins are a major component of the mammalian nuclear lamina, a dense fibrous protein meshwork located in the nuclear interior. Lamin A/C proteins regulate nuclear mechanics and structure and control cellular signaling, gene transcription, epigenetic regulation, cell cycle progression, cell differentiation, and cell migration. The immune system is composed of the innate and adaptive branches. Innate immunity is mediated by myeloid cells such as neutrophils, macrophages, and dendritic cells. These cells produce a rapid and nonspecific response through phagocytosis, cytokine production, and complement activation, as well as activating adaptive immunity. Specific adaptive immunity is activated by antigen presentation by antigen presenting cells (APCs) and the cytokine microenvironment, and is mainly mediated by the cellular functions of T cells and the production of antibodies by B cells. Unlike most cell types, immune cells regulate their lamin A/C protein expression relatively rapidly to exert their functions, with expression increasing in macrophages, reducing in neutrophils, and increasing transiently in T cells. In this review, we discuss and summarize studies that have addressed the role played by lamin A/C in the functions of innate and adaptive immune cells in the context of human inflammatory and autoimmune diseases, pathogen infections, and cancer. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Open AccessReview
Vimentin as a Multifaceted Player and Potential Therapeutic Target in Viral Infections
Int. J. Mol. Sci. 2020, 21(13), 4675; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134675 - 30 Jun 2020
Cited by 8
Abstract
Vimentin is an intermediate filament protein that plays key roles in integration of cytoskeletal functions, and therefore in basic cellular processes such as cell division and migration. Consequently, vimentin has complex implications in pathophysiology. Vimentin is required for a proper immune response, but [...] Read more.
Vimentin is an intermediate filament protein that plays key roles in integration of cytoskeletal functions, and therefore in basic cellular processes such as cell division and migration. Consequently, vimentin has complex implications in pathophysiology. Vimentin is required for a proper immune response, but it can also act as an autoantigen in autoimmune diseases or as a damage signal. Although vimentin is a predominantly cytoplasmic protein, it can also appear at extracellular locations, either in a secreted form or at the surface of numerous cell types, often in relation to cell activation, inflammation, injury or senescence. Cell surface targeting of vimentin appears to associate with the occurrence of certain posttranslational modifications, such as phosphorylation and/or oxidative damage. At the cell surface, vimentin can act as a receptor for bacterial and viral pathogens. Indeed, vimentin has been shown to play important roles in virus attachment and entry of severe acute respiratory syndrome-related coronavirus (SARS-CoV), dengue and encephalitis viruses, among others. Moreover, the presence of vimentin in specific virus-targeted cells and its induction by proinflammatory cytokines and tissue damage contribute to its implication in viral infection. Here, we recapitulate some of the pathophysiological implications of vimentin, including the involvement of cell surface vimentin in interaction with pathogens, with a special focus on its role as a cellular receptor or co-receptor for viruses. In addition, we provide a perspective on approaches to target vimentin, including antibodies or chemical agents that could modulate these interactions to potentially interfere with viral pathogenesis, which could be useful when multi-target antiviral strategies are needed. Full article
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Unidirectional regulation of vimentin intermediate filaments to caveolin-1

Abstract: Both the mechanosensitive vimentin cytoskeleton and endocytic caveolae contribute to active processes such as cell migration, morphogenesis and stress response. However, the crosstalk between these two systems has remained elusive. Here, we find that there is mutual exclusive subcellular expression between vimentin and cavolin-1, and vimentin filaments interact and arrest the cytoplasmic motility of caveolin-1. Importantly, vimentin depletion induces phosphorylation of caviloin-1 on Tyr14, and consequently, restores the compromised cell migration rete and directionality caused by caveolin-1 deprivation. Moreover, vimentin knockout further recovers the reduced intracellular motility of caveolin-1 upon hypo-osmotic shock. In contrary, caveolin-1 depletion has no effect on the expression, phosphorylation on Ser39, Ser 56 and Ser83, distribution, solubility, and cellular dynamics of vimentin. Taken together, our data reveals a one-way regulation of vimentin to caveolin-1, at least on the cellular level.

Title: Keratins are upregulated during hypoxia and complex with and modulate Hif1α signaling in colonic epithelia.

Title: Keratin 7 as a constituent of the keratin network in mouse pancreatic islets.

 
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