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

Sci Adv. 2019 May 8;5(5):eaau8857. doi: 10.1126/sciadv.aau8857.

M Di Rienzo ¹ ², M Antonioli ¹, C Fusco ³, Y Liu ⁴, M Mari ⁵, I Orhon ⁵, G Refolo ¹, F Germani ¹, M Corazzari ⁶, A Romagnoli ¹, F Ciccosanti ¹, B Mandriani ³, M T Pellico ³, R De La Torre ⁴, H Ding ⁷, M Dentice ⁸, M Neri ⁹, A Ferlini ⁹, F Reggiori ⁵, M Kulesz-Martin ⁴ ¹⁰, M Piacentini ¹ ², G Merla ³, G M Fimia ¹ ¹¹

Affiliations

1 National Institute for Infectious Diseases IRCCS, Lazzaro Spallanzani, 00149 Rome, Italy.
2 Department of Biology, University of Rome, Tor Vergata, 00133 Rome, Italy.
3 Division of Medical Genetics, IRCCS, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.
4 Department of Dermatology, Oregon Health and Science University, Portland, OR 97239, USA.
5 Department of Biomedical Sciences of Cells and Systems, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, Netherlands.
6 Department of Health Sciences, University of Piemonte Orientale "A. Avogadro", Novara, Novara, Italy.
7 Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
8 Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy.
9 Section of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
10 Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR 97239, USA.
11 Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce 73100, Italy.

PMID: 31123703 DOI: 10.1126/sciadv.aau8857

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.

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