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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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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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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Supplementary Information
Supplementary Figures 1–9 and Supplementary Table legends
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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DOI: https://doi.org/10.1038/s41556-017-0024-9
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