Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Intermediate filaments: from cell architecture to nanomechanics

Key Points

  • Intermediate filaments (IFs) are assembled from fibrous proteins that exhibit a central α-helical rod domain with a conserved substructure. This rod domain facilitates the formation of dimeric coiled-coil complexes.

  • In metazoan cells, IF proteins constitute two distinct filament systems: one in the nucleus and one in the cytoplasm. In both cases, the major function of these filaments is thought to be the buffering of mechanical stress.

  • In conjunction with associated proteins, IFs generate networks that serve to generate and support the shape of cells.

  • Recent nanomechanical experiments have demonstrated that IFs are characterized by a high propensity to withstand both tensile and bending stress.

  • In line with this, disease mutations in human IF proteins indicate that the nanomechanical properties of cell-type-specific IFs are central to the pathogenesis of these diseases.

  • Apart from structural functions, the analysis of complex diseases, such as cardiomyopathies, has revealed that IFs also have a significant role in cell-type-specific physiological functions and even contribute to the regulation of gene-expression programmes.

Abstract

Intermediate filaments (IFs) constitute a major structural element of animal cells. They build two distinct systems, one in the nucleus and one in the cytoplasm. In both cases, their major function is assumed to be that of a mechanical stress absorber and an integrating device for the entire cytoskeleton. In line with this, recent disease mutations in human IF proteins indicate that the nanomechanical properties of cell-type-specific IFs are central to the pathogenesis of diseases as diverse as muscular dystrophy and premature ageing. However, the analysis of these various diseases suggests that IFs also have an important role in cell-type-specific physiological functions.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Intermediate filament organization in metazoan cells.
Figure 2: Structural model of cytoplasmic and nuclear intermediate filament protein dimers.
Figure 3: Destruction of muscle architecture in desminopathy.
Figure 4: Overview of the assembly and decay pathway of various desmin mutants.
Figure 5: Hypothetical scheme for the disease mechanism caused by desmin mutations.

Similar content being viewed by others

References

  1. Goldman, R. D., Milsted, A., Schloss, J. A., Starger, J. & Yerna, M. J. Cytoplasmic fibers in mammalian cells: cytoskeletal and contractile elements. Annu. Rev. Physiol. 41, 703–722 (1979).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Fuchs, E. & Weber, K. Intermediate filaments: structure, dynamics, function, and disease. Annu. Rev. Biochem. 63, 345–382 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Herrmann, H., Hesse, M., Reichenzeller, M., Aebi, U. & Magin, T. M. Functional complexity of intermediate filament cytoskeletons: from structure to assembly to gene ablation. Int. Rev. Cytol. 223, 83–175 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Omary, M. B., Coulombe, P. A. & McLean, W. H. Intermediate filament proteins and their associated diseases. N. Engl. J. Med. 351, 2087–2100 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Capell, B. C. & Collins, F. S. Human laminopathies: nuclei gone genetically awry. Nature Rev. Genet. 7, 940–952 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Green, K. J., Bohringer, M., Gocken, T. & Jones, J. C. Intermediate filament associated proteins. Adv. Protein Chem. 70, 143–202 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Bershadsky, A. D., Balaban, N. Q. & Geiger, B. Adhesion-dependent cell mechanosensitivity. Annu. Rev. Cell Dev. Biol. 19, 677–695 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Herrmann, H. & Aebi, U. Intermediate filaments: molecular structure, assembly mechanism, and integration into functionally distinct intracellular scaffolds. Annu. Rev. Biochem. 73, 749–789 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Goldman, R. D., Khuon, S., Chou, Y. H., Opal, P. & Steinert, P. M. The function of intermediate filaments in cell shape and cytoskeletal integrity. J. Cell Biol. 134, 971–983 (1996). The injection of peptides that represent coil 1A of vimentin into fibroblasts leads to the disassembly of IFs, followed by a massive reorganization of the whole cytoskeleton and alterations of cellular shape.

    Article  CAS  PubMed  Google Scholar 

  11. Gruenbaum, Y., Margalit, A., Goldman, R. D., Shumaker, D. K. & Wilson, K. L. The nuclear lamina comes of age. Nature Rev. Mol. Cell Biol. 6, 21–31 (2005).

    Article  CAS  Google Scholar 

  12. Tzur, Y. B., Wilson, K. L. & Gruenbaum, Y. SUN-domain proteins: 'Velcro' that links the nucleoskeleton to the cytoskeleton. Nature Rev. Mol. Cell Biol. 7, 782–788 (2006).

    Article  CAS  Google Scholar 

  13. Roper, K., Gregory, S. L. & Brown, N. H. The 'spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families. J. Cell Sci. 115, 4215–4225 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Wilhelmsen, K. et al. Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin. J. Cell Biol. 171, 799–810 (2005). The outer nuclear membrane protein nesprin-3 is shown to bind to and recruit plectin to the nuclear periphery, suggesting that a continuous connection between the nucleus and the extracellular matrix is mediated with the help of the IF cytoskeleton and the integrin system.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jefferson, J. J., Leung, C. L. & Liem, R. K. Plakins: goliaths that link cell junctions and the cytoskeleton. Nature Rev. Mol. Cell Biol. 5, 542–553 (2004).

    Article  CAS  Google Scholar 

  16. Maniotis, A. J., Chen, C. S. & Ingber, D. E. Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure. Proc. Natl Acad. Sci. USA 94, 849–854 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen, C. S., Tan, J. & Tien, J. Mechanotransduction at cell–matrix and cell–cell contacts. Annu. Rev. Biomed. Eng. 6, 275–302 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Langbein, L. et al. Characterization of a novel human type II epithelial keratin K1b, specifically expressed in eccrine sweat glands. J. Invest. Dermatol. 125, 428–444 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Kartenbeck, J., Schwechheimer, K., Moll, R. & Franke, W. W. Attachment of vimentin filaments to desmosomal plaques in human meningiomal cells and arachnoidal tissue. J. Cell Biol. 98, 1072–1081 (1984).

    Article  CAS  PubMed  Google Scholar 

  20. Franke, W. W., Borrmann, C. M., Grund, C. & Pieperhoff, S. The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins. Eur. J. Cell Biol. 85, 69–82 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Gerull, B. et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nature Genet. 36, 1162–1164 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Grossmann, K. S. et al. Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation. J. Cell Biol. 167, 149–160 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. DePianto, D. & Coulombe, P. A. Intermediate filaments and tissue repair. Exp. Cell Res. 301, 68–76 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Aebi, U., Cohn, J., Buhle, L. & Gerace, L. The nuclear lamina is a meshwork of intermediate-type filaments. Nature 323, 560–564 (1986).

    Article  CAS  PubMed  Google Scholar 

  25. Foeger, N. et al. Solubility properties and specific assembly pathways of the B-type lamin from Caenorhabditis elegans. J. Struct. Biol. 155, 340–350 (2006). Characterizes the solution state of several forms of recombinant lamins and shows that lamin assembly can progress extremely fast in vitro compared with the assembly of cytoplasmic IF protein vimentin.

    Article  CAS  PubMed  Google Scholar 

  26. Steinert, P. M., Marekov, L. N., Fraser, R. D. & Parry, D. A. Keratin intermediate filament structure. Crosslinking studies yield quantitative information on molecular dimensions and mechanism of assembly. J. Mol. Biol. 230, 436–452 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Izawa, I. & Inagaki, M. Regulatory mechanisms and functions of intermediate filaments: a study using site- and phosphorylation state-specific antibodies. Cancer Sci. 97, 167–174 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Ip, W., Hartzer, M. K., Pang, Y. Y. & Robson, R. M. Assembly of vimentin in vitro and its implications concerning the structure of intermediate filaments. J. Mol. Biol. 183, 365–375 (1985).

    Article  CAS  PubMed  Google Scholar 

  29. Herrmann, H. et al. Structure and assembly properties of the intermediate filament protein vimentin: The role of its head, rod and tail domains. J. Mol. Biol. 264, 933–953 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Helfand, B. T., Chang, L. & Goldman, R. D. The dynamic and motile properties of intermediate filaments. Annu. Rev. Cell Dev. Biol. 19, 445–467 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Samarel, A. M. Costameres, focal adhesions, and cardiomyocyte mechanotransduction. Am. J. Physiol. Heart Circ. Physiol. 289, H2291–H2301 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Bhosle, R. C., Michele, D. E., Campbell, K. P., Li, Z. & Robson, R. M. Interactions of intermediate filament protein synemin with dystrophin and utrophin. Biochem. Biophys. Res. Commun. 346, 768–777 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Uyama, N. et al. Hepatic stellate cells express synemin, a protein bridging intermediate filaments to focal adhesions. Gut 55, 1276–1289 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kasza, K. E. et al. The cell as a material. Curr. Opin. Cell Biol. 19, 101–107 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Sokolova, A. V. et al. Monitoring intermediate filament assembly by small-angle x-ray scattering reveals the molecular architecture of assembly intermediates. Proc. Natl Acad. Sci. USA 103, 16206–16211 (2006). The first study of vimentin assembly in solution using small-angle X-ray scattering, which led to 3D molecular models of tetramers, octamers and the ULFs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Herrmann, H., Haner, M., Brettel, M., Ku, N. O. & Aebi, U. Characterization of distinct early assembly units of different intermediate filament proteins. J. Mol. Biol. 286, 1403–1420 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Kirmse, R. et al. A quantitative kinetic model for the in vitro assembly of intermediate filaments from tetrameric vimentin. J. Biol. Chem. 2 Apr 2007 (doi:10.1074/jbc.M701063200).

    Article  CAS  Google Scholar 

  38. Panorchan, P., Schafer, B. W., Wirtz, D. & Tseng, Y. Nuclear envelope breakdown requires overcoming the mechanical integrity of the nuclear lamina. J. Biol. Chem. 279, 43462–43467 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Windoffer, R., Kolsch, A., Woll, S. & Leube, R. E. Focal adhesions are hotspots for keratin filament precursor formation. J. Cell Biol. 173, 341–348 (2006). The regulatory potential of focal adhesions for keratin IF assembly is demonstrated, and this property provides a basis for the coordinated shaping of the cytoskeleton during structural reorganization events of the cell.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Goldman, A. E., Moir, R. D., Montag-Lowy, M., Stewart, M. & Goldman, R. D. Pathway of incorporation of microinjected lamin A into the nuclear envelope. J. Cell Biol. 119, 725–735 (1992).

    Article  CAS  PubMed  Google Scholar 

  41. Moir, R. D., Spann, T. P., Herrmann, H. & Goldman, R. D. Disruption of nuclear lamin organization blocks the elongation phase of DNA replication. J. Cell Biol. 149, 1179–1192 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mücke, N., Kirmse, R., Wedig, T., Leterrier, J. F. & Kreplak, L. Investigation of the morphology of intermediate filaments adsorbed to different solid supports. J. Struct. Biol. 150, 268–276 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Mücke, N. et al. Assessing the flexibility of intermediate filaments by atomic force microscopy. J. Mol. Biol. 335, 1241–1250 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Storm, C., Pastore, J. J., MacKintosh, F. C., Lubensky, T. C. & Janmey, P. A. Nonlinear elasticity in biological gels. Nature 435, 191–194 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Park, A. C. & Baddiel, C. B. Rheology of the stratum corneum: a molecular interpretation of the stress-strain curve. J. Soc. Cosmet. Chem. 23, 3–12 (1972).

    Google Scholar 

  46. Fudge, D. S. & Gosline, J. M. Molecular design of the α-keratin composite: insights from a matrix-free model, hagfish slime threads. Proc. Biol. Sci. 271, 291–299 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Parbhu, A. N., Bryson, W. G. & Lal, R. Disulfide bonds in the outer layer of keratin fibers confer higher mechanical rigidity: correlative nano-indentation and elasticity measurement with an AFM. Biochemistry 38, 11755–11761 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Kreplak, L., Bär, H., Leterrier, J. F., Herrmann, H. & Aebi, U. Exploring the mechanical behavior of single intermediate filaments. J. Mol. Biol. 354, 569–577 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Janmey, P. A., Euteneuer, U., Traub, P. & Schliwa, M. Viscoelastic properties of vimentin compared with other filamentous biopolymer networks. J. Cell Biol. 113, 155–160 (1991).

    Article  CAS  PubMed  Google Scholar 

  50. Kreplak, L. & Fudge, D. Biomechanical properties of intermediate filaments: from tissues to single filaments and back. Bioessays 29, 26–35 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Tsuda, Y., Yasutake, H., Ishijima, A. & Yanagida, T. Torsional rigidity of single actin filaments and actin-actin bond breaking force under torsion measured directly by in vitro micromanipulation. Proc. Natl Acad. Sci. USA 93, 12937–12942 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Brangwynne, C. P. et al. Microtubules can bear enhanced compressive loads in living cells because of lateral reinforcement. J. Cell Biol. 173, 733–741 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Esue, O., Carson, A. A., Tseng, Y. & Wirtz, D. A direct interaction between actin and vimentin filaments mediated by the tail domain of vimentin. J. Biol. Chem. 281, 30393–30399 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Hohenadl, M., Storz, T., Kirpal, H., Kroy, K. & Merkel, R. Desmin filaments studied by quasi-elastic light scattering. Biophys. J. 77, 2199–2209 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bao, G. & Suresh, S. Cell and molecular mechanics of biological materials. Nature Mater. 2, 715–725 (2003).

    Article  CAS  Google Scholar 

  56. Wang, N., Butler, J. P. & Ingber, D. E. Mechanotransduction across the cell surface and through the cytoskeleton. Science 260, 1124–1127 (1993).

    Article  CAS  PubMed  Google Scholar 

  57. Sadoshima, J. & Izumo, S. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J. 12, 1681–1692 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Omary, M. B., Ku, N. O., Tao, G. Z., Toivola, D. M. & Liao, J. “Heads and tails” of intermediate filament phosphorylation: multiple sites and functional insights. Trends Biochem. Sci. 31, 383–394 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Gu, L. H. & Coulombe, P. A. Keratin function in skin epithelia: a broadening palette with surprising shades. Curr. Opin. Cell Biol. 19, 13–23 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Ingber, D. E. Cellular mechanotransduction: putting all the pieces together again. FASEB J. 20, 811–827 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Colucci-Guyon, E. et al. Mice lacking vimentin develop and reproduce without an obvious phenotype. Cell 79, 679–694 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Terzi, F. et al. Reduction of renal mass is lethal in mice lacking vimentin. Role of endothelin-nitric oxide imbalance. J. Clin. Invest. 100, 1520–1528 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Schiffers, P. M. et al. Altered flow-induced arterial remodeling in vimentin-deficient mice. Arterioscler. Thromb. Vasc. Biol. 20, 611–616 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Davies, P. F., Spaan, J. A. & Krams, R. Shear stress biology of the endothelium. Ann. Biomed. Eng. 33, 1714–1718 (2005).

    Article  PubMed  Google Scholar 

  65. Runembert, I. et al. Recovery of Na–glucose cotransport activity after renal ischemia is impaired in mice lacking vimentin. Am. J. Physiol. Renal Physiol. 287, F960–F968 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Colucci-Guyon, E., Gimenez, Y. R. M., Maurice, T., Babinet, C. & Privat, A. Cerebellar defect and impaired motor coordination in mice lacking vimentin. Glia 25, 33–43 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Perlson, E. et al. Vimentin-dependent spatial translocation of an activated MAP kinase in injured nerve. Neuron 45, 715–726 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Nieminen, M. et al. Vimentin function in lymphocyte adhesion and transcellular migration. Nature Cell Biol. 8, 156–162 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Lane, E. B. & McLean, W. H. Keratins and skin disorders. J. Pathol. 204, 355–366 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Goldfarb, L. G., Vicart, P., Goebel, H. H. & Dalakas, M. C. Desmin myopathy. Brain 127, 723–734 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Bonne, G. et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nature Genet. 21, 285–288 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Worman, H. J. & Courvalin, J. C. Nuclear envelope, nuclear lamina, and inherited disease. Int. Rev. Cytol. 246, 231–279 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Mounkes, L. C. & Stewart, C. L. Aging and nuclear organization: lamins and progeria. Curr. Opin. Cell Biol. 16, 322–327 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Gotzmann, J. & Foisner, R. A-type lamin complexes and regenerative potential: a step towards understanding laminopathic diseases? Histochem. Cell Biol. 125, 33–41 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Li, R., Messing, A., Goldman, J. E. & Brenner, M. GFAP mutations in Alexander disease. Int. J. Dev. Neurosci. 20, 259–268 (2002).

    Article  PubMed  Google Scholar 

  76. Der Perng, M. et al. The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of αB-crystallin and HSP27. Am. J. Hum. Genet. 79, 197–213 (2006). Describes the consequences of an Arg to Trp mutation in GFAP. Specifically, impaired assembly leading to protein aggregation and chaperone sequestration are shown to represent early events in Alexander disease.

    Article  PubMed  Google Scholar 

  77. Jamora, C. & Fuchs, E. Intercellular adhesion, signalling and the cytoskeleton. Nature Cell Biol. 4, E101–E108 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Clark, K. A., McElhinny, A. S., Beckerle, M. C. & Gregorio, C. C. Striated muscle cytoarchitecture: an intricate web of form and function. Annu. Rev. Cell Dev. Biol. 18, 637–706 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Bär, H. et al. Severe muscle disease-causing desmin mutations interfere with in vitro filament assembly at distinct stages. Proc. Natl Acad. Sci. USA 102, 15099–15104 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bär, H. et al. Impact of disease mutations on the desmin filament assembly process. J. Mol. Biol. 360, 1031–1042 (2006). The structural implications for the polymorphism of IFs generated by mutant desmin are revealed using several biophysical methods, including analytical ultracentrifugation, viscometry and scanning transmission electron microscopy.

    Article  CAS  PubMed  Google Scholar 

  81. Bär, H., Mücke, N., Katus, H. A., Aebi, U. & Herrmann, H. Assembly defects of desmin disease mutants carrying deletions in the α-helical rod domain are rescued by wild type protein. J. Struct. Biol. 158, 107–115 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Bär, H. et al. Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies. Hum. Mutat. 28, 374–386 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Bär, H. et al. Forced expression of desmin and desmin mutants in cultured cells: impact of myopathic missense mutations in the central coiled-coil domain on network formation. Exp. Cell Res. 312, 1554–1565 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Chen, Q. et al. Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake. Circ. Res. 97, 1018–1026 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Liu, J. et al. Impairment of the ubiquitin-proteasome system in desminopathy mouse hearts. FASEB J. 20, 362–364 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Sanbe, A. et al. Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy. Proc. Natl Acad. Sci. USA 102, 13592–13597 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Milner, D. J., Mavroidis, M., Weisleder, N. & Capetanaki, Y. Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function. J. Cell Biol. 150, 1283–1298 (2000). Physiological studies with muscle derived from desmin-null mice demonstrate that desmin IFs are important for proper mitochondrial positioning and respiratory function in cardiac and skeletal muscle.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Maloyan, A. et al. Mitochondrial dysfunction and apoptosis underlie the pathogenic process in α-B-crystallin desmin-related cardiomyopathy. Circulation 112, 3451–3461 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Davies, K. E. & Nowak, K. J. Molecular mechanisms of muscular dystrophies: old and new players. Nature Rev. Mol. Cell Biol. 7, 762–773 (2006).

    Article  CAS  Google Scholar 

  90. Lieber, R. L., Thornell, L. E. & Friden, J. Muscle cytoskeletal disruption occurs within the first 15 min of cyclic eccentric contraction. J. Appl. Physiol. 80, 278–284 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Shah, S. B. et al. Structural and functional roles of desmin in mouse skeletal muscle during passive deformation. Biophys. J. 86, 2993–3008 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Li, Z. et al. Cardiovascular lesions and skeletal myopathy in mice lacking desmin. Dev. Biol. 175, 362–366 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Milner, D. J., Weitzer, G., Tran, D., Bradley, A. & Capetanaki, Y. Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. J. Cell Biol. 134, 1255–1270 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Thornell, L., Carlsson, L., Li, Z., Mericskay, M. & Paulin, D. Null mutation in the desmin gene gives rise to a cardiomyopathy. J. Mol. Cell. Cardiol. 29, 2107–2124 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Weisleder, N., Taffet, G. E. & Capetanaki, Y. Bcl-2 overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy. Proc. Natl Acad. Sci. USA 101, 769–774 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Capetanaki, Y. Desmin cytoskeleton: a potential regulator of muscle mitochondrial behavior and function. Trends Cardiovasc. Med. 12, 339–348 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Haubold, K. W., Allen, D. L., Capetanaki, Y. & Leinwand, L. A. Loss of desmin leads to impaired voluntary wheel running and treadmill exercise performance. J. Appl. Physiol. 95, 1617–1622 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Steinert, P. M. & Roop, D. R. Molecular and cellular biology of intermediate filaments. Annu. Rev. Biochem. 57, 593–625 (1988).

    Article  CAS  PubMed  Google Scholar 

  99. Strelkov, S. V. et al. Conserved segments 1A and 2B of the intermediate filament dimer: their atomic structures and role in filament assembly. EMBO J. 21, 1255–1266 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Parry, D. A. Hendecad repeat in segment 2A and linker L2 of intermediate filament chains implies the possibility of a right-handed coiled-coil structure. J. Struct. Biol. 155, 370–374 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Hess, J. F., Budamagunta, M. S., Shipman, R. L., FitzGerald, P. G. & Voss, J. C. Characterization of the linker 2 region in human vimentin using site-directed spin labeling and electron paramagnetic resonance. Biochemistry 45, 11737–11743 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Müller, D. J., Schabert, F. A., Buldt, G. & Engel, A. Imaging purple membranes in aqueous solutions at sub-nanometer resolution by atomic force microscopy. Biophys. J. 68, 1681–1686 (1995).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Kiss, B., Karsai, A. & Kellermayer, M. S. Nanomechanical properties of desmin intermediate filaments. J. Struct. Biol. 155, 327–339 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Kis, A. et al. Nanomechanics of microtubules. Phys. Rev. Lett. 89, 248101 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Guzman, C. et al. Exploring the mechanical properties of single vimentin intermediate filaments by atomic force microscopy. J. Mol. Biol. 360, 623–630 (2006). Using AFM, the bending modulus of non-stabilized single vimentin IFs, hanging over a porous membrane, was determined by elastic deformation with the tip of the microscope cantilever.

    Article  CAS  PubMed  Google Scholar 

  106. Bär, H. et al. Pathogenic effects of a novel heterozygous R350P desmin mutation on the assembly of desmin intermediate filaments in vivo and in vitro. Hum. Mol. Genet. 14, 1251–1260 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge support from the German Research Foundation (H.H. and H.B.), the Swiss Society for Research on Muscular Diseases (U.A. and S.V.S.), the National Centre of Competence in Research program on 'Nanoscale Science', the Swiss National Science Foundation, the M.E. Müller Foundation of Switzerland and the Canton Basel-Stadt (all to U.A.), Group Biomedical Sciences and the Research Council of the Catholic University of Leuven (S.V.S.) and the European Union FP6 Life Science, Genomics and Biotechnology for Health area (H.H. and U.A.).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Harald Herrmann or Ueli Aebi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Alexander disease

Hutchinson–Gilford progeria syndrome

myofibrillar myopathy

Werner syndrome

FURTHER INFORMATION

Human Intermediate Filament Database

Euro Laminopathies — nuclear envelope-linked rare human diseases: from molecular pathophysiology towards clinical applications

Glossary

Desmosome

A submembraneous, dense protein plaque that is composed of proteins such as desmoplakin to anchor intermediate filaments tightly. Desmosomes connect to identical structures of neighbouring cells via specific transmembrane proteins of the cadherin type.

Adherens junction

A microfilament-anchoring plaque structure made from α- and β-catenin, plakoglobin and the C-terminal domains of classical cadherins, the extracellular domains of which bind in a calcium-dependent manner to similar proteins on neighbouring cells.

Gap junction

A protein channel made from connexins that connects neighbouring cells and only lets pass molecules with a mass of 1,000 Da.

Tight junction

A band-like, complex protein assembly that is built from polypeptides called claudins and occludins that resides in-between the plasma membranes of neighbouring cells. Tight junctions mediate a tight linkage of cell layers so that no solutes can pass.

Microfilament

A cytoplasmic filament, with a 9-nm diameter, that is made from the globular protein actin. Depending on the cellular environment, microfilaments can be complexed with different sets of actin-binding proteins.

Collagen

A fibril of high tensile strength made from hydroxyproline-rich triple-helical fibrous proteins. Collagen is the most abundant component in the extracellular matrix of metazoan cells.

Hemidesmosome

A submembraneous plaque structure that connects the basal lamina via transmembrane proteins of the integrin type with intermediate filaments.

Focal adhesion

A cell attachment and signalling structure that uses integrins to connect and integrate the extracellular matrix with the cytoplasmic microfilament system.

Lamin

The nuclear intermediate filament protein that constitutes the basic structural element of the nuclear lamina; that is, the proteinaceous scaffold that supports the inner nuclear membrane and that connects it to chromatin.

Heterochromatin

Segments of chromatin in eukaryotic cells that are highly condensed, transcriptionally repressed and that replicate late during interphase.

MAN1

The MAN antigens are three inner nuclear membrane proteins that were discovered with the help of auto-antibodies isolated from a patient with a collagen vascular disease. MAN1 has the highest molecular weight (80,000 Da).

Spectraplakin family

Multifunctional cross-bridging proteins, encoded by the BPAG1 and MACF1 genes, of up to 9,000 amino acids that share features with both the spectrin and plakin superfamilies and have many isoforms that are generated by differential splicing of their mRNAs.

Costamere

A periodic rib-like region of the membrane cytoskeleton that contains actin-binding proteins such as vinculin, α- and β-spectrins, plectin and integrins. Costameres co-distribute with Z- and M-lines and provide a membrane linkage for the subsarcolemmal myofibrils. They are mechanically coupled to Z-disks by desmin filaments.

Dynamic shear modulus

The shear modulus is a measure of the stiffness of a solid block when a force is applied parallel to one of its surfaces while the opposite surface is fixed to a support. When an oscillatory force is applied, a dynamic shear modulus is measured.

Elastic modulus

For linearly elastic materials, the slope of the stress–strain curve is often referred to as the Young's modulus or the elastic modulus.

Epidermolytic diseases

A group of inherited skin disorders that are characterized by blistering of the epidermis as a result of minor mechanical trauma. In these diseases, blister cleavage occurs in the plane of the epidermis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herrmann, H., Bär, H., Kreplak, L. et al. Intermediate filaments: from cell architecture to nanomechanics. Nat Rev Mol Cell Biol 8, 562–573 (2007). https://doi.org/10.1038/nrm2197

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2197

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing