Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy.
During muscle atrophy, myofibrillar proteins are degraded in an ordered process in which MuRF1 catalyzes ubiquitylation of thick filament components (Cohen et al. 2009. J. Cell Biol. http://dx.doi.org/10.1083/jcb.200901052). Here, we show that another ubiquitin ligase, Trim32, ubiquitylates thin filament (actin, tropomyosin, troponins) and Z-band (α-actinin) components and promotes their degradation. Down-regulation of Trim32 during fasting reduced fiber atrophy and the rapid loss of thin filaments. Desmin filaments were proposed to maintain the integrity of thin filaments. Accordingly, we find that the rapid destruction of thin filament proteins upon fasting was accompanied by increased phosphorylation of desmin filaments, which promoted desmin ubiquitylation by Trim32 and degradation. Reducing Trim32 levels prevented the loss of both desmin and thin filament proteins. Furthermore, overexpression of an inhibitor of desmin polymerization induced disassembly of desmin filaments and destruction of thin filament components. Thus, during fasting, desmin phosphorylation increases and enhances Trim32-mediated degradation of the desmin cytoskeleton, which appears to facilitate the breakdown of Z-bands and thin filaments.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Shenhav
S
Cohen
Bo
B
Zhai
Steven P
SP
Gygi
Alfred L
AL
Goldberg
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D003893:Desmin / Q000378:metabolism*; D005215:Fasting / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology*; D009210:Myofibrils / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000502:physiology; D012518:Sarcomeres / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
D000199:Actins; D003893:Desmin; C514011:TRIM32 protein, mouse; D044767:Ubiquitin-Protein Ligases