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Post-translational modifications of intermediate filament proteins: mechanisms and functions

Nature Reviews Molecular Cell Biology volume 15, pages 163–177 (2014)Cite this article

Subjects

Key Points

  • Intermediate filament (IF) proteins comprise a large family of tissue-specific cytoskeletal proteins that include the nuclear IFs (lamins) and cytoplasmic IFs (keratins, vimentin, desmin, peripherin, glial fibrillary acidic protein, neurofilaments (NFs), nestin, filensin, phakinin, synemin and syncoilin). Mutations in genes encoding IF proteins cause or predispose to more than 80 human diseases.

  • IF proteins undergo several post-translational modifications (PTMs), including phosphorylation, glycosylation, sumoylation, acetylation, prenylation, ubiquitylation and transamidation, which regulate each other through crosstalk and binding of IFs to other proteins. Prenylation is found exclusively in lamins, whereas most of the remaining modifications involve both cytoplasmic and nuclear IFs.

  • IF phosphorylation is a multifunctional PTM that regulates axonal transport (NFs), cell growth and stress responses (keratins), nuclear viral egress and nucleocytoplasmic transport of ribonucleoproteins (lamins), neuromuscular development (nestin), epithelial-to-mesenchymal transition and cell migration (vimentin and keratins).

  • IF sumoylation has been identified in lamins, keratins and vimentin, but is likely to involve most, if not all, IFs. Low-level sumoylation promotes IF solubility, whereas hypersumoylation inhibits it. Hypersumoylation is found in stress and disease contexts.

  • Other functional roles for IF PTMs include sensing of the metabolic environment (acetylation), regulation of IF turnover (ubiquitylation), regulation of cell survival mechanisms and protein–protein interactions (glycosylation and phosphorylation), association with the nuclear membrane (farnesylation) and formation of the cornified envelope in the skin (transamidation).

  • IFs undergo considerable disease-associated PTM changes that may manifest as site-specific decreases or increases. An increase in a site-specific PTM is exemplified by IF hyperphosphorylation (a stress marker in many diseases), IF hyperubiquitylation (due to proteasome inhibition) and IF transamidation (found in hepatocyte Mallory–Denk body inclusions). IF PTMs are attractive candidates as biomarkers of human disease and potential therapeutic targets.

Abstract

Intermediate filaments (IFs) are cytoskeletal and nucleoskeletal structures that provide mechanical and stress-coping resilience to cells, contribute to subcellular and tissue-specific biological functions, and facilitate intracellular communication. IFs, including nuclear lamins and those in the cytoplasm (keratins, vimentin, desmin, neurofilaments and glial fibrillary acidic protein, among others), are functionally regulated by post-translational modifications (PTMs). Proteomic advances highlight the enormous complexity and regulatory potential of IF protein PTMs, which include phosphorylation, glycosylation, sumoylation, acetylation and prenylation, with novel modifications becoming increasingly appreciated. Future studies will need to characterize their on–off mechanisms, crosstalk and utility as biomarkers and targets for diseases involving the IF cytoskeleton.

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Figure 1: Cytoplasmic IF assembly and reorganization in response to phosphorylation and other PTMs.
Figure 2: Multifunctional roles for IF protein phosphorylation.
Figure 3: IF protein sumoylation regulates filament organization and solubility properties.
Figure 4: Mechanisms of IF PTM functions and crosstalk.

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Acknowledgements

The authors' work is supported by US National Institutes of Health grants DK47918 and DK52951 (M.B.O.), DK093776 (N.T.S.) and a Department of Veterans Affairs Merit Review Award (M.B.O.).

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Authors and Affiliations

  1. Departments of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Natasha T. Snider & M. Bishr Omary

  2. Internal Medicine, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    M. Bishr Omary

  3. Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, 48109, Michigan, USA

    M. Bishr Omary

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Glossary

Malonylation

Covalent addition of a malonyl group (CO-CH2-CO) to protein Lys residues.

Hutchinson–Gilford progeria syndrome

(HGPS). A genetic condition linked to lamin A (LMNA) mutations and characterized by premature ageing that begins in early childhood.

Dilated cardiomyopathy

(DCM). Lamin A(LMNA)-linked autosomal dominant disease that is characterized by cardiac dilatation and impaired systolic function. It is the major cause of heart transplants in young patients.

Familial partial lipodystrophy

A metabolic disorder that involves abnormal distribution of subcutaneous adipose tissue and can also lead to insulin-resistant diabetes.

Hemidesmosome

A cell-to-substrate attachment site that contains keratin IFs, plectin and α6β4 integrin, among other proteins that bind to extracellular matrix components, such as laminin 5 and type VII collagen.

Alexander disease

(AxD). A rare early-onset neurodegenerative disease that involves destruction of myelin and is caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP).

Amyotrophic lateral sclerosis

A progressive neurodegenerative disease, affecting motor neurons, which is mostly sporadic and caused by mutations in less than 10% of cases.

Steatohepatitis

Inflammation and fat accumulation in the liver that is most frequently triggered by alcohol consumption or obesity.

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Snider, N., Omary, M. Post-translational modifications of intermediate filament proteins: mechanisms and functions. Nat Rev Mol Cell Biol 15, 163–177 (2014). https://doi.org/10.1038/nrm3753

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