Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains

M. Di Rienzo, M. Antonioli, C. Fusco, Y. Liu, M. Mari, I. Orhon, G. Refolo, F. Germani, M. Corazzari, A. Romagnoli, F. Ciccosanti, B. Mandriani, M. T. Pellico, R. De La Torre, H. Ding, M. Dentice, M. Neri, A. Ferlini, F. Reggiori, M. Kulesz-MartinM. Piacentini, G. Merla, G. M. Fimia

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32's ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.

Original languageEnglish (US)
Article numbereaau8857
JournalScience Advances
Volume5
Issue number5
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Physics and Astronomy (miscellaneous)
  • General

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    Di Rienzo, M., Antonioli, M., Fusco, C., Liu, Y., Mari, M., Orhon, I., Refolo, G., Germani, F., Corazzari, M., Romagnoli, A., Ciccosanti, F., Mandriani, B., Pellico, M. T., De La Torre, R., Ding, H., Dentice, M., Neri, M., Ferlini, A., Reggiori, F., ... Fimia, G. M. (2019). Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains. Science Advances, 5(5), [eaau8857]. https://doi.org/10.1126/sciadv.aau8857