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The MTM1–UBQLN2–HSP complex mediates degradation of misfolded intermediate filaments in skeletal muscle

Nature Cell Biology volume 20, pages 198–210 (2018)Cite this article

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Abstract

The ubiquitin proteasome system and autophagy are major protein turnover mechanisms in muscle cells, which ensure stemness and muscle fibre maintenance. Muscle cells contain a high proportion of cytoskeletal proteins, which are prone to misfolding and aggregation; pathological processes that are observed in several neuromuscular diseases called proteinopathies. Despite advances in deciphering the mechanisms underlying misfolding and aggregation, little is known about how muscle cells manage cytoskeletal degradation. Here, we describe a process by which muscle cells degrade the misfolded intermediate filament proteins desmin and vimentin by the proteasome. This relies on the MTM1–UBQLN2 complex to recognize and guide these misfolded proteins to the proteasome and occurs prior to aggregate formation. Thus, our data highlight a safeguarding function of the MTM1–UBQLN2 complex that ensures cytoskeletal integrity to avoid proteotoxic aggregate formation.

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Fig. 1: MTM1 and UBQLN2 regulate proteotoxic stress in muscle cells.
Fig. 2: MTM1 and UBQLN2 are required for the degradation of intermediate filaments in muscle cells.
Fig. 3: MTM1 or UBQLN2 depletion in vivo affects intermediate filament dynamics in skeletal muscle.
Fig. 4: The absence of MTM1 impaired intermediate filament degradation and UBQLN2 localization in human samples.
Fig. 5: Mapping the UBQLN2 binding site on MTM1 and the effect of mutations found in XLCNM on degradation of intermediate filaments.
Fig. 6: MTM1–UBQLN2 binding is required to maintain muscle mass in vivo.
Fig. 7: Impaired MTM1–UBQLN2-mediated degradation promotes endoplasmic reticulum stress and induces maladaptive UPR.
Fig. 8: MTM1 affected UBQLN2 ERAD function in muscle cells.

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Acknowledgements

We thank the IGBMC technical platforms (animal facility, electron and confocal microscopy) and C. Kretz for their technical assistance, C. Sellier, N. Dali-Youssef, F. Alpy and H. E. Magliarelli for sharing antibodies and other materials, L. Beilscmidt for technical assistance, M. Mendoza Parra and F. Colin for their help with modelling, F. Gaits-Iacovoni, A. Lewis for manuscript editing and B. Payrastre for his support. We acknowledge funding from INSERM (K.H.), the Scientific Council of the University of Strasbourg (K.H.), the AFM (Association Française contre la Myopathy) (AFM-20879 to K.H., AFM-15352 to J.L.) and grant ANR-10-LABX-0030-INRT, awarded as part of the Investissements d’Avenir ANR-10-IDEX-0002-02 framework.

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Author notes

  1. Christos Gavriilidis and Leila Laredj contributed equally to this work.

Authors and Affiliations

  1. Department of Translational Medicine and Neurogenetics, IGBMC, Illkirch, France

    Christos Gavriilidis, Leila Laredj, Jocelyn Laporte & Karim Hnia

  2. INSERM U964, Illkirch, France

    Christos Gavriilidis, Leila Laredj, Nadia Messaddeq, Jocelyn Laporte, Izabela Sumara & Karim Hnia

  3. CNRS UMR7104, Illkirch, France

    Christos Gavriilidis, Leila Laredj, Nadia Messaddeq, Jocelyn Laporte, Izabela Sumara & Karim Hnia

  4. Strasbourg University, Illkirch, France

    Christos Gavriilidis, Leila Laredj, Nadia Messaddeq, Jocelyn Laporte, Izabela Sumara & Karim Hnia

  5. INSERM, UMR1048, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France

    Romain Solinhac, Julien Viaud & Karim Hnia

  6. Department of Development and Stem Cells, IGBMC, Illkirch, France

    Izabela Sumara

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Contributions

C.G. and L.L. performed experiments, analysed data, interpreted results and edited the manuscript. N.M. performed TEM experiments and interpreted the results. J.L. conceived the Y2H experiment, provided material, discussed the data and edited the manuscript. J.V., R.S. and I.S. provided materials, discussed the data and edited the manuscript. K.H. conceived the project, designed and performed experiments, interpreted results, wrote and edited the manuscript.

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Correspondence to Karim Hnia.

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Supplementary information

Supplementary Information

Supplementary Figures 1–9 and Supplementary Table legends

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Supplementary Table 1

MTM1 interactors in skeletal muscle.

Supplementary Table 2

List of antibodies used in this study.

Supplementary Table 3

List of primers.

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Gavriilidis, C., Laredj, L., Solinhac, R. et al. The MTM1–UBQLN2–HSP complex mediates degradation of misfolded intermediate filaments in skeletal muscle. Nat Cell Biol 20, 198–210 (2018). https://doi.org/10.1038/s41556-017-0024-9

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