title: Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy.
abstract: BECLIN 1 is a central player in macroautophagy. AMBRA1, a BECLIN 1-interacting protein, positively regulates the BECLIN 1-dependent programme of autophagy. In this study, we show that AMBRA1 binds preferentially the mitochondrial pool of the antiapoptotic factor BCL-2, and that this interaction is disrupted following autophagy induction. Further, AMBRA1 can compete with both mitochondrial and endoplasmic reticulum-resident BCL-2 (mito-BCL-2 and ER-BCL-2, respectively) to bind BECLIN 1. Moreover, after autophagy induction, AMBRA1 is recruited to BECLIN 1. Altogether, these results indicate that, in normal conditions, a pool of AMBRA1 binds preferentially mito-BCL-2; after autophagy induction, AMBRA1 is released from BCL-2, consistent with its ability to promote BECLIN 1 activity. In addition, we found that the binding between AMBRA1 and mito-BCL-2 is reduced during apoptosis. Thus, a dynamic interaction exists between AMBRA1 and BCL-2 at the mitochondria that could regulate both BECLIN 1-dependent autophagy and apoptosis.
authors.affiliation: Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Flavie
authors.initials: F
authors.lastname: Strappazzon
authors.forename: Matteo
authors.initials: M
authors.lastname: Vietri-Rudan
authors.forename: Silvia
authors.initials: S
authors.lastname: Campello
authors.forename: Francesca
authors.initials: F
authors.lastname: Nazio
authors.forename: Fulvio
authors.initials: F
authors.lastname: Florenzano
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fimia
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D002352:Carrier Proteins / Q000096:biosynthesis*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D025941:Protein Interaction Mapping; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: C553334:AMBRA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D002352:Carrier Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2