A TRIM32-AMBRA1-ULK1 complex initiates the autophagy response in atrophic muscle cells

Research output: Contribution to journalComment/debatepeer-review

Abstract

The Ser/Thr protein kinase ULK1 is an upstream macroautophagy/autophagy regulator that is rapidly activated to ensure a proper adaptive response to stress conditions. Signaling pathways modulating ULK1 activity have been extensively characterized in response to nutrient/energy shortage, which mainly act by mediating ULK1 post-translational modifications, such as phosphorylation, acetylation and ubiquitination. Less characterized is how tissue-specific stress signals are able to activate ULK1 to induce autophagy. Our recent study has uncovered the E3 ubiquitin ligase TRIM32 as a novel ULK1 activator that regulates autophagy in muscle cells upon atrophy induction. TRIM32 is conveyed to ULK1 by the autophagy cofactor AMBRA1 to stimulate its kinase activity through unanchored K63-linked polyubiquitin chains. Notably, mutations in TRIM32 responsible for limb-girdle muscular dystrophy 2H disrupt its ability to bind ULK1 and to induce autophagy in muscle cells, resulting in a dysregulated activation of the atrophic process. In conclusion, we have identified a novel molecular mechanism by which autophagy is regulated in muscles, whose alteration is associated with the development of muscular dystrophy.

Original languageEnglish
Pages (from-to)1-3
Number of pages3
JournalAutophagy
DOIs
Publication statusE-pub ahead of print - Jun 25 2019

Keywords

  • AMBRA1
  • muscle atrophy
  • muscular dystrophy
  • TRIM32
  • Tripartite Motif Protein
  • ULK1
  • unanchored polyubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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