2. Academic Validation
  3. AMBRA1 interplay with cullin E3 ubiquitin ligases regulates autophagy dynamics

AMBRA1 interplay with cullin E3 ubiquitin ligases regulates autophagy dynamics

  • Dev Cell. 2014 Dec 22;31(6):734-46. doi: 10.1016/j.devcel.2014.11.013.
Manuela Antonioli 1,  Federica Albiero 1,  Francesca Nazio 2,  Tiziana Vescovo 3,  Ariel Basulto Perdomo 3,  Marco Corazzari 1,  Claudia Marsella 1,  Pierluca Piselli 3,  Christine Gretzmeier 4,  Jörn Dengjel 4,  Francesco Cecconi 5,  Mauro Piacentini 6,  Gian Maria Fimia 7
Affiliations

Affiliations

  • 1 National Institute for Infectious Diseases "L. Spallanzani" IRCCS, 00149 Rome, Italy; Department of Biology, University of Rome "Tor Vergata," 00173 Rome, Italy.
  • 2 Dulbecco Telethon Institute at the Department of Biology, University of Rome "Tor Vergata," 00173 Rome, Italy; Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
  • 3 National Institute for Infectious Diseases "L. Spallanzani" IRCCS, 00149 Rome, Italy.
  • 4 Department of Dermatology, University Freiburg Medical Center, 79104 Freiburg, Germany; ZBSA Center for Biological Systems Analysis, University of Freiburg, 79104 Freiburg, Germany.
  • 5 Dulbecco Telethon Institute at the Department of Biology, University of Rome "Tor Vergata," 00173 Rome, Italy; Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen Ø, Denmark.
  • 6 National Institute for Infectious Diseases "L. Spallanzani" IRCCS, 00149 Rome, Italy; Department of Biology, University of Rome "Tor Vergata," 00173 Rome, Italy. Electronic address: [email protected].
  • 7 National Institute for Infectious Diseases "L. Spallanzani" IRCCS, 00149 Rome, Italy; Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce 73100, Italy. Electronic address: [email protected].
PMID: 25499913 DOI: 10.1016/j.devcel.2014.11.013
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.

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