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

Christos Gavriilidis; Leila Laredj; Romain Solinhac; Nadia Messaddeq; Julien Viaud; Jocelyn Laporte; Izabela Sumara; Karim Hnia

doi:10.1038/s41556-017-0024-9

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

Nat Cell Biol. 2018 Feb;20(2):198-210. doi: 10.1038/s41556-017-0024-9. Epub 2018 Jan 22.

Authors

Christos Gavriilidis^{1

2

3

4}, Leila Laredj^{1

2

3

4}, Romain Solinhac⁵, Nadia Messaddeq^{2

3

4}, Julien Viaud⁵, Jocelyn Laporte^{1

2

3

4}, Izabela Sumara^{2

3

4

6}, Karim Hnia^{7

8

9

10

11}

Affiliations

¹ Department of Translational Medicine and Neurogenetics, IGBMC, Illkirch, France.
² INSERM U964, Illkirch, France.
³ CNRS UMR7104, Illkirch, France.
⁴ Strasbourg University, Illkirch, France.
⁵ INSERM, UMR1048, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France.
⁶ Department of Development and Stem Cells, IGBMC, Illkirch, France.
⁷ Department of Translational Medicine and Neurogenetics, IGBMC, Illkirch, France. karim.hnia@inserm.fr.
⁸ INSERM U964, Illkirch, France. karim.hnia@inserm.fr.
⁹ CNRS UMR7104, Illkirch, France. karim.hnia@inserm.fr.
¹⁰ Strasbourg University, Illkirch, France. karim.hnia@inserm.fr.
¹¹ INSERM, UMR1048, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France. karim.hnia@inserm.fr.

PMID: 29358706
DOI: 10.1038/s41556-017-0024-9

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Autophagy / genetics*
Autophagy-Related Proteins
Cell Cycle Proteins / chemistry
Cell Cycle Proteins / genetics*
Cytoskeleton / genetics
Desmin / genetics
Humans
Intermediate Filament Proteins / chemistry
Intermediate Filament Proteins / genetics*
Muscle, Skeletal / chemistry
Muscle, Skeletal / metabolism
Proteasome Endopeptidase Complex / chemistry
Proteasome Endopeptidase Complex / genetics
Protein Aggregates / genetics
Protein Folding
Protein Tyrosine Phosphatases, Non-Receptor / chemistry
Protein Tyrosine Phosphatases, Non-Receptor / genetics*
Proteolysis
Ubiquitin / genetics
Ubiquitins / chemistry
Ubiquitins / genetics*
Vimentin / genetics

Substances

Adaptor Proteins, Signal Transducing
Autophagy-Related Proteins
Cell Cycle Proteins
Desmin
Intermediate Filament Proteins
Protein Aggregates
UBQLN2 protein, human
Ubiquitin
Ubiquitins
Vimentin
Protein Tyrosine Phosphatases, Non-Receptor
myotubularin
Proteasome Endopeptidase Complex