Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response

V. Pagliarini, E. Wirawan, A. Romagnoli, F. Ciccosanti, G. Lisi, S. Lippens, F. Cecconi, G. M. Fimia, P. Vandenabeele, M. Corazzari, M. Piacentini

Research output: Contribution to journalArticle

Abstract

Under stress conditions, pro-survival and pro-death processes are concomitantly activated and the final outcome depends on the complex crosstalk between these pathways. In most cases, autophagy functions as an early-induced cytoprotective response, favoring stress adaptation by removing damaged subcellular constituents. Moreover, several lines of evidence suggest that autophagy inactivation by the apoptotic machinery is a crucial event for cell death execution. Here we show that apoptotic stimuli induce a rapid decrease in the level of the autophagic factor Activating Molecule in Beclin1-Regulated Autophagy (Ambra1). Ambra1 degradation is prevented by concomitant inhibition of caspases and calpains. By both in vitro and in vivo approaches, we demonstrate that caspases are responsible for Ambra1 cleavage at the D482 site, whereas calpains are involved in complete Ambra1 degradation. Finally, we show that Ambra1 levels are critical for the rate of apoptosis induction. RNA interference-mediated Ambra1 downregulation further sensitizes cells to apoptotic stimuli, while Ambra1 overexpression and, more efficiently, a caspase non-cleavable mutant counteract cell death by prolonging autophagy induction. We conclude that Ambra1 is an important target of apoptotic proteases resulting in the dismantling of the autophagic machinery and the accomplishment of the cell death program.

Original languageEnglish
Pages (from-to)1495-1504
Number of pages10
JournalCell Death and Differentiation
Volume19
Issue number9
DOIs
Publication statusPublished - Sep 2012

Keywords

  • Ambra1
  • apoptosis
  • autophagy
  • calpains
  • caspases

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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