Intermediate Filaments

Abstract

Intermediate filaments (IFs) represent a diverse group of evolutionary conserved cytoskeletal structures, with context‐, tissue‐ and cell type‐dependent expression patterns and properties. Initially, IFs were assumed to provide only structural reinforcement in cells and tissues. However, recent research has rapidly expanded the knowledge of the functions of IF proteins, and the view of this complex gene family is progressively changing, as a multitude of diseases have been revealed to be associated with IF mutations. The molecular mechanisms underlying these disease conditions reflect disturbances in molecular processes reaching far beyond structural support. IFs are now known to be multifunctional organisers of cellular processes during all stages of life, from development to ageing, with critical functions in both homoeostasis and stress.

Key Concepts:

  • Intermediate filaments are flexible cytoskeletal and nucleoskeletal structures that assemble hierarchically.

  • Intermediate filaments comprise a diverse protein family expressed in a differentiation stage‐, cell‐ and tissue‐specific manner.

  • Intermediate filaments are functionally regulated by posttranslational modifications (PTMs).

  • Intermediate filaments integrate cell fate control with mechanosensing and three‐dimensional arrangement of cells and tissues.

  • Intermediate filaments are modulators of cell signalling and transcription.

  • Intermediate filaments are important cellular stress proteins that help in maintaining the cellular organisation and homoeostasis on injury.

  • Intermediate filaments act at the border between health and disease as critical guardian biopolymers, the failing of which contributes to a diverse range of pathologies.

Keywords: intermediate filaments (IFs); cytoskeleton; signal transduction; transcriptional regulation; posttranslational modifications (PTMs); cell differentiation; tissue homoeostasis; vimentin; keratin; nestin; lamin

Figure 1.

Representative organisation of intermediate filaments in a mammalian cell. Illustration depicting a mammalian epithelial cell model, where the three key cytoskeletal filament systems, microfilaments (MFs), microtubules (MTs) and intermediate filaments (IFs), are connected to each other by plakin‐type linker molecules, such as plectin. IFs are also coupled to IF‐anchoring plaques of cell–cell junctions (desmosomes) and to cell–matrix junctions (hemidesmosomes) by these plakin‐type protein complexes. Focal adhesions are formed through IF complexes at the base to the extracellular matrix (ECM). The transmembrane proteins that mediate the contact with the neighbouring cells and with ECM are cadherins and integrins, respectively. Cytoskeletal filaments are, furthermore, coupled to both inner and outer nuclear membrane (INM and ONM) by Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. On the inner side of the nuclear envelope, nuclear IF proteins, lamins, are depicted as being concentrated in the lamina and also distributed throughout the nucleoplasm. Lamins interact with INM proteins, such as emerin and nesprin, nuclear pore complex (NPC), various nucleoplasmic factors, such as LAP2, as well as chromatin. Lamins interact with cytoskeletal IFs, which in turn associate with nuclear membrane proteins, thereby providing a mechanical continuum reaching from the ECM to chromatin. ER, endoplasmic reticulum; MTOC, microtubule‐organizing center.

Figure 2.

Intermediate filament structure and assembly. (a) Schematic representation of the structural organisation of an IF molecule, consisting of an N‐terminal head domain (Red box), the central α‐helical rod domain (grey boxes including coils 1A, 1B, 2A and 2B) and a C‐terminal tail domain (green box). Site‐specific phosphorylation of head and tail domain residues is a major facilitator of IF reorganisation, although other posttranslational modifications (PTMs) are also likely to have a role. (b) Coil–coil homodimerization or heterodimerization. (c) Two IF dimers assemble in an antiparallel fashion to form soluble tetramers. (d) Eight tetrameric subunits further associate laterally to form unit‐length filaments (ULF). (e) ULFs and short filaments longitudinally assemble and elongate through end‐to‐end annealing. (f) Filaments have radially compacted to a diameter of approximately 11 nm of mature IFs. AcLys, Lys acetylation; C, caspase cleavage; F, farnesylation; Gly, O‐linked glycosylation; P, phosphorylation; SUMO, sumoylation; T, transamidation; Ub, ubiquitylation.

Figure 3.

General disease mechanisms caused by IF mutations. Individual or multiple mutations of an intermediate filament (IF) molecule can affect different biophysical properties of the filaments (purple boxes), which in turn can interfere with distinct cellular activities (green boxes). Consequently, different physiological responses would be deregulated at the cellular or tissue level (yellow boxes). Ultimately, these cellular events cause various tissue‐wide pathogenic alterations from apoptosis to heart failure (blue boxes).

close

References

Bonne G, Di Barletta MR, Varnous S et al. (1999) Mutations in the gene encoding lamin A/C cause autosomal dominant Emery‐Dreifuss muscular dystrophy. Nature Genetics 21: 285–288.

Challa AA and Stefanovic B (2011) A novel role of vimentin filaments: binding and stabilization of collagen mRNAs. Molecular and Cellular Biology 31: 3773–3789.

Chen H, Chen X and Zheng Y (2013) The nuclear lamina regulates germline stem cell niche organization via modulation of EGFR signaling. Cell Stem Cell 13: 73–86.

Chernoivanenko IS and Minin AA (2013) Role of vimentin in cell migration. Ontogenez 44: 186–202.

Cheung KJ, Gabrielson E, Werb Z and Ewald AJ (2013) Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155: 1639–1651.

Chung BM, Rotty JD and Coulombe PA (2013) Networking galore: intermediate filaments and cell migration. Current Opinion in Cell Biology 25: 600–612.

Colakoglu G and Brown A (2009) Intermediate filaments exchange subunits along their length and elongate by end‐to‐end annealing. Journal of Cell Biology 185: 769–777.

Coulombe PA and Wong P (2004) Cytoplasmic intermediate filaments revealed as dynamic and multipurpose scaffolds. Nature Cell Biology 6: 699–706.

Eriksson JE, Dechat T, Grin B et al. (2009) Introducing intermediate filaments: from discovery to disease. Journal of Clinical Investigation 119: 1763–1771.

Fatkin D, MacRae C, Sasaki T et al. (1999) Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction‐system disease. New England Journal of Medicine 341: 1715–1724.

Goto H and Inagaki M (2014) New insights into roles of intermediate filament phosphorylation and progeria pathogenesis. IUBMB Life. doi:10.1002/iub.1260.

Guelen L, Pagie L, Brasset E et al. (2008) Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453: 948–951.

Guo Y, Kim Y, Shimi T, Goldman RD and Zheng Y (2014) Concentration‐dependent lamin assembly and its roles in the localization of other nuclear proteins. Molecular Biology of the Cell 25: 1287–1297.

Herrmann H, Bar H, Kreplak L, Strelkov SV and Aebi U (2007) Intermediate filaments: from cell architecture to nanomechanics. Nature Reviews Molecular Cell Biology 8: 562–573.

Herrmann H, Strelkov SV, Burkhard P and Aebi U (2009) Intermediate filaments: primary determinants of cell architecture and plasticity. Journal of Clinical Investigation 119: 1772–1783.

Ho CY, Jaalouk DE, Vartiainen MK and Lammerding J (2013) Lamin A/C and emerin regulate MKL1‐SRF activity by modulating actin dynamics. Nature 497: 507–511.

Hyder CL, Isoniemi KO, Torvaldson ES and Eriksson JE (2011) Insights into intermediate filament regulation from development to ageing. Journal of Cell Science 124: 1363–1372.

Ishikawa H, Bischoff R and Holtzer H (1968) Mitosis and intermediate‐sized filaments in developing skeletal muscle. Journal of Cell Biology 38: 538–555.

Kim S and Coulombe PA (2007) Intermediate filament scaffolds fulfill mechanical, organizational, and signaling functions in the cytoplasm. Genes & Development 21: 1581–1597.

Kim S and Coulombe PA (2010) Emerging role for the cytoskeleton as an organizer and regulator of translation. Nature Reviews Molecular Cell Biology 11: 75–81.

Kim S, Kellner J, Lee CH and Coulombe PA (2007) Interaction between the keratin cytoskeleton and eEF1Bgamma affects protein synthesis in epithelial cells. Nature Structural & Molecular Biology 14: 982–983.

Kochin V, Shimi T, Torvaldson E et al. (2014) Interphase phosphorylation of lamin A. Journal of Cell Science 127: 2683–2696.

Kwak HI, Kang H, Dave JM et al. (2012) Calpain‐mediated vimentin cleavage occurs upstream of MT1‐MMP membrane translocation to facilitate endothelial sprout initiation. Angiogenesis 15: 287–303.

Lazarides E (1980) Intermediate filaments as mechanical integrators of cellular space. Nature 283: 249–256.

Lepinoux‐Chambaud C and Eyer J (2013) Review on intermediate filaments of the nervous system and their pathological alterations. Histochemistry and Cell Biology 140: 13–22.

Lessard JC, Pina‐Paz S, Rotty JD et al. (2013) Keratin 16 regulates innate immunity in response to epidermal barrier breach. Proceedings of the National Academy of Sciences of the United States of America 110: 19537–19542.

Liem RK and Messing A (2009) Dysfunctions of neuronal and glial intermediate filaments in disease. Journal of Clinical Investigation 119: 1814–1824.

Lutolf MP and Hubbell JA (2005) Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nature Biotechnology 23: 47–55.

Matsuyama M, Tanaka H, Inoko A et al. (2013) Defect of mitotic vimentin phosphorylation causes microophthalmia and cataract via aneuploidy and senescence in lens epithelial cells. Journal of Biological Chemistry 288: 35626–35635.

Middeldorp J and Hol EM (2011) GFAP in health and disease. Progress in Neurobiology 93: 421–443.

Mor‐Vaknin N, Legendre M, Yu Y et al. (2013) Murine colitis is mediated by vimentin. Scientific Reports 3: 1045–1058.

Nieminen M, Henttinen T, Merinen M et al. (2006) Vimentin function in lymphocyte adhesion and transcellular migration. Nature Cell Biology 8: 156–162.

Nussinov R, Tsai CJ, Xin F and Radivojac P (2012) Allosteric post‐translational modification codes. Trends in Biochemical Sciences 37: 447–455.

Obermajer N, Doljak B and Kos J (2009) Cytokeratin 8 ectoplasmic domain binds urokinase‐type plasminogen activator to breast tumor cells and modulates their adhesion, growth and invasiveness. Molecular Cancer 8: 88–100.

Pallari HM, Lindqvist J, Torvaldson E et al. (2011) Nestin as a regulator of Cdk5 in differentiating myoblasts. Molecular Biology of the Cell 22: 1539–1549.

Pan X, Hobbs RP and Coulombe PA (2013) The expanding significance of keratin intermediate filaments in normal and diseased epithelia. Current Opinion in Cell Biology 25: 47–56.

Qin Z, Kreplak L and Buehler MJ (2009) Hierarchical structure controls nanomechanical properties of vimentin intermediate filaments. PLoS One 4: e7294.

Roth W, Reuter U, Wohlenberg C, Bruckner‐Tuderman L and Magin TM (2009) Cytokines as genetic modifiers in K5‐/‐ mice and in human epidermolysis bullosa simplex. Human Mutation 30: 832–841.

Schreiber KH and Kennedy BK (2013) When lamins go bad: nuclear structure and disease. Cell 152: 1365–1375.

Simon DN and Wilson KL (2013) Partners and post‐translational modifications of nuclear lamins. Chromosoma 122: 13–31.

Snider NT and Omary MB (2014) Post‐translational modifications of intermediate filament proteins: mechanisms and functions. Nature Reviews Molecular Cell Biology 15: 163–177.

Stacey SN, Sulem P, Masson G et al. (2009) New common variants affecting susceptibility to basal cell carcinoma. Nature Genetics 41: 909–914.

Swift J, Ivanovska IL, Buxboim A et al. (2013) Nuclear lamin‐A scales with tissue stiffness and enhances matrix‐directed differentiation. Science 341: 1240104.

Teshigawara K, Kuboyama T, Shigyo M et al. (2013) A novel compound, denosomin, ameliorates spinal cord injury via axonal growth associated with astrocyte‐secreted vimentin. British Journal of Pharmacology 168: 903–919.

Teunissen CE and Khalil M (2012) Neurofilaments as biomarkers in multiple sclerosis. Multiple Sclerosis Journal 18: 552–556.

Vuoriluoto K, Haugen H, Kiviluoto S et al. (2011) Vimentin regulates EMT induction by Slug and oncogenic H‐Ras and migration by governing Axl expression in breast cancer. Oncogene 30: 1436–1448.

Wang N, Butler JP and Ingber DE (1993) Mechanotransduction across the cell surface and through the cytoskeleton. Science 260: 1124–1127.

Wang RC, Wei Y, An Z et al. (2012) Akt‐mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338: 956–959.

Further Reading

Buckley IK, Raju TR and Stewart M (1978) Heavy‐meromyosin labeling of intermediate filaments in cultured connective‐tissue cells. Journal of Cell Biology 78: 644–652.

Franke WW, Schmid E, Osborn M and Weber K (1978) Different intermediate‐sized filaments distinguished by immunofluorescence microscopy. Proceedings of the National Academy of Sciences of the United States of America 75: 5034–5038.

Gurtner GC, Werner S, Barrandon Y and Longaker MT (2008) Wound repair and regeneration. Nature 453: 314–321.

Herrmann H and Strelkov SV (2011) History and phylogeny of intermediate filaments: now in insects. BMC Biology 9: 16.

Homberg M and Magin TM (2014) Beyond expectations: novel insights into epidermal keratin function and regulation. International Review of Cell and Molecular Biology 311: 265–306.

Karantza V (2011) Keratins in health and cancer: more than mere epithelial cell markers. Oncogene 30: 127–138.

Moll R, Divo M and Langbein L (2008) The human keratins: biology and pathology. Histochemistry and Cell Biology 129: 705–733.

Satelli A and Li SL (2011) Vimentin in cancer and its potential as a molecular target for cancer therapy. Cellular and Molecular Life Sciences 68: 3033–3046.

Szeverenyi I, Cassidy AJ, Chung CW et al. (2008) The Human Intermediate Filament Database: comprehensive information on a gene family involved in many human diseases. Human Mutation 29: 351–360.

Toivola DM, Strnad P, Habtezion A and Omary MB (2010) Intermediate filaments take the heat as stress proteins. Trends in Cell Biology 20: 79–91.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Cheng, Fang, and Eriksson, John E(Dec 2014) Intermediate Filaments. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001259.pub2]