AMBRA1 interplay with cullin E3 Ubiquitin ligases regulates autophagy dynamics

Manuela Antonioli, Federica Albiero, Francesca Nazio, Tiziana Vescovo, ArielBasulto Perdomo, Marco Corazzari, Claudia Marsella, Pierluca Piselli, Christine Gretzmeier, Jörn Dengjel, Francesco Cecconi, Mauro Piacentini, GianMaria Fimia

Research output: Contribution to journalArticlepeer-review

Abstract

Autophagy maintains cellular homeostasis by degrading harmful or unnecessary intracellular components. How the autophagy response is induced rapidly and transiently remains largely unknown. We report that the E3 ubiquitin ligases Cullin-5 and Cullin-4 regulate the onset and termination of autophagy, respectively, by dynamically interacting with AMBRA1, a regulator of autophagy. Under normal conditions, Cullin-4 binding to AMBRA1 limits its protein abundance. Autophagy stimuli promote AMBRA1 stabilization by causing ULK1-dependent Cullin-4 release. Notably, Cullin-4/AMBRA1 dissociation is transient, and the re-established interaction triggers AMBRA1 degradation, terminating the autophagy response. Moreover, Cullin-4 inhibits the interaction between AMBRA1 and another Cullin E3 ligase. Indeed, upon Cullin-4 dissociation, AMBRA1 binds and inhibits Cullin-5, thus promoting the accumulation of the mTOR inhibitor DEPTOR. Through DEPTOR stabilization, AMBRA1 establishes a feedback loop that ensures the rapid onset of autophagy by enhancing mTOR inactivation. Our findings show that Cullin-mediated degradation of autophagy regulators temporally controls the autophagy response.

Original languageEnglish
Pages (from-to)734-746
Number of pages13
JournalDevelopmental Cell
Volume31
Issue number6
DOIs
Publication statusPublished - Dec 22 2014

ASJC Scopus subject areas

  • Developmental Biology
  • Medicine(all)

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