Home > B. Cellular pathology > intermediate filaments

intermediate filaments

Monday 10 November 2003

Cytoplasmic intermediate filaments (IF) can be divided into 5 subclasses based on their biochemical properties, immunologic specificity and tissue distribution: keratins in epithelial cells, vimentin, desmin in muscle cells, glial filaments (GFAP) in astrocytes, and neurofilaments in neurons. The different types of intermediate filament proteins share common structural features.

Intermediate filament proteins constitute a highly diverse family of fibrous proteins in metazoans, which assemble into 10-nm-thick filaments in the cytoplasm and the nucleus. The in vitro assembly mechanism have revealed principal differences in the formation of cytoplasmic and nuclear filaments.

Intermediate filaments are a structurally related family of cellular proteins that appear to be intimately involved with the cytoskeleton. The intermediate filaments are built up of rope-like polymers composed of protein subunits with linear a-helical content, and form a complex family of five different groups of filaments, one of which is the epithelial filaments.

Structure

The different sequence data show that the intermediate filament proteins contain a similar alpha-helical domain of conserved length capable of forming coiled-coils.

The common structural motif shared by all IFs is a central alpha-helical ’rod domain’ flanked by variable N- and C-terminal domains. The rod domain, the canonical feature of IFs, has been highly conserved during evolution. The variable terminals, however, have allowed the known IFs to be classified into 6 distinct types by virtue of their differing amino acid sequences.

Types

- Types I and II

  • cytokeratins (keratins)

- Type III

  • desmin
  • vimentin (MIM.193060)
  • GFAP (MIM.137780) (mutations in Alexander disease MIM.203450)
  • peripherin

- Type IV

  • neurofilaments

- Type V

  • nuclear lamins

- Type VI

  • nestin (MIM.600915)

The vimentin, desmin, and glial fibrillary acidic protein genes each contains 8 introns at identical positions, 6 of the introns being located within the regions encoding alpha-helical sequences. A majority of the introns in the less closely related keratin genes occurred at similar or identical positions.

Localization

- cytoplasmic filaments
- nuclear filaments

Functions

- Intermediate filament proteins (IFs) maintain cell and tissue integrity, based on evidence of their polymerization and mechanical properties, abundance and disease-associated phenotypes. This ’traditional’ function is now augmented by organelle-related and protein-targeting roles.

Mitochondrial location and function depend on intact IFs, as demonstrated for desmin, keratins and neurofilaments. Golgi positioning is regulated by several IFs, and endosomal/lysosomal protein distribution by vimentin.

IFs dramatically affect nuclear function and shape and play a role in subcellular and membrane targeting of proteins. These functions have been noted in tissues but in some cases only in cell culture.

The IF-related organelle-specific and protein-targeting roles, which are likely interrelated, provide functions beyond cell scaffolding and integrity and contribute to the cytoprotective and tissue-specific functions of IF proteins.

- signal transduction

Pathology

- intermediate filament-related dermatopathies (fibrillar dermatopathies)

  • pathology of cytokeratins (keratinopathies)

- intermediate filament-related myopathies (myofibrillar myopathies)
- intermediate filament-related neuropathies

  • intermediate filaments accumulations in amyotrophic lateral sclerosis (ALS) and neurodegeneration
  • neurofilament gene mutations linked to ALS and Charcot-Marie-Tooth disease (CMT2E)
  • GFAP mutations in Alexander disease

By systems

- intermediate filaments in neuropathology

  • Five major types of intermediate filament proteins are expressed in mature neurons: the three neurofilament proteins (NF-L, NF-M, and NF-H), alpha-internexin, and peripherin.

See also

- intermediate filament inclusion bodies
- intermediate filament polypeptides
- interactions with molecular motors

  • conventional kinesin
  • cytoplasmic dynein
  • myosin

References

- Godsel LM, Hobbs RP, Green KJ. Intermediate filament assembly: dynamics to disease. Trends Cell Biol. 2008 Jan;18(1):28-37. PMID: 18083519

- Herrmann H, Bar H, Kreplak L, Strelkov SV, Aebi U. Intermediate filaments: from cell architecture to nanomechanics. Nat Rev Mol Cell Biol. 2007 Jul;8(7):562-73. PMID: 17551517

- Helfand BT, Chou YH, Shumaker DK, Goldman RD. Intermediate filament proteins participate in signal transduction. Trends Cell Biol. 2005 Nov;15(11):568-70. PMID: 16213139

- Toivola DM, Tao GZ, Habtezion A, Liao J, Omary MB. Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments.Trends Cell Biol. 2005 Nov;15(11):608-17. PMID: 16202602

- Omary MB, Coulombe PA, McLean WH. Intermediate filament proteins and their associated diseases. N Engl J Med. 2004 Nov 11;351(20):2087-100. PMID: 15537907

- Coulombe PA, Wong P. Cytoplasmic intermediate filaments revealed as dynamic and multipurpose scaffolds. Nat Cell Biol. 2004 Aug;6(8):699-706. PMID: 15303099

- Intermediate filaments mediate cytoskeletal crosstalk. Nat Rev Mol Cell Biol. 2004 Aug;5(8):601-13. PMID: 15366704

- Lariviere RC, Julien JP. Functions of intermediate filaments in neuronal development and disease. J Neurobiol. 2004 Jan;58(1):131-48. Review. PMID: 14598376

- Helfand BT, Chang L, Goldman RD. The dynamic and motile properties of intermediate filaments. Annu Rev Cell Dev Biol. 2003;19:445-67. PMID: 14570577

- Herrmann H, Foisner R. Intermediate filaments: novel assembly models and exciting new functions for nuclear lamins.Cell Mol Life Sci. 2003 Aug;60(8):1607-12. PMID: 14504651

- Herrmann H, Hesse M, Reichenzeller M, Aebi U, Magin TM. Functional complexity of intermediate filament cytoskeletons: from structure to assembly to gene ablation. Int Rev Cytol. 2003;223:83-175. PMID: 12641211

- Coulombe PA, Bousquet O, Ma L, Yamada S, Wirtz D. The ’ins’ and ’outs’ of intermediate filament organization. Trends Cell Biol. 2000 Oct;10(10):420-8. PMID: 10998598

- Fuchs E, Cleveland DW: A structural scaffolding of intermediate filaments in health and disease. Science 279:514, 1998.

- Lee MK, Cleveland DW. Neuronal intermediate filaments. Annu Rev Neurosci. 1996;19:187-217. PMID: 8833441

- Cadrin M, Martinoli MG. Alterations of intermediate filaments in various histopathological conditions. Biochem Cell Biol. 1995 Sep-Oct;73(9-10):627-34. PMID: 8714682

- - Klymkowsky MW: Intermediate filaments: new proteins, some answers, more questions. Current Opinion in Cell Biol 1995;7:46-54.

- Fuchs E, Weber K: Intermediate filaments: Structure, dynamics, function and disease. Annu Rev Biochem 1994;63:345-382.

- Fuchs E. Intermediate filaments and disease: mutations that cripple cell strength. J Cell Biol. 1994 May;125(3):511-6. PMID: 7513705

- Heins S, Aebi U. Making heads and tails of intermediate filament assembly, dynamics and networks. Curr Opin Cell Biol. 1994 Feb;6(1):25-33. PMID: 8167022

- Steinert PM, Roop DR: Molecular and cellular biology of intermediate filaments. Ann Rev Biochem 1988;57:593-625.

- Lazarides E: Intermediate filaments as mechanical integrators of cellular space. Nature 1980;283:249-256.

- Moll R, Franke WW, Schiller D, et al: The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells-review. Cell 1982;31:11-24.

- Osborn M, Weber K: Intermediate filaments: cell-type-specific markers in differentiation and pathology. Cell 1982;31:303-306.

- Parry DA, Steinert PM. Intermediate filament structure. Curr Opin Cell Biol. 1992 Feb;4(1):94-8. PMID: 1373068

- Intermediate filaments in biology and disease. Revis Biol Celular. 1989;22:1-80. PMID: 2699767

- Mayer RJ, Lowe J, Lennox G, Doherty F, Landon M. Intermediate filaments and ubiquitin: a new thread in the understanding of chronic neurodegenerative diseases. Prog Clin Biol Res. 1989;317:809-18. PMID: 2557642