Prosurvival AMBRA1 turns into a proapoptotic BH3-like protein during mitochondrial apoptosis.
Autophagy and apoptosis are 2 stress-response mechanisms that are closely interconnected. However, the molecular interplays between these 2 pathways remain to be clarified. Here we report that the crucial proautophagic factor AMBRA1 can act as a positive mediator of mitochondrial apoptosis. Indeed, we show that, in a proapoptotic positive feedback loop, the C-terminal part of AMBRA1, generated by CASP/CASPASE cleavage upon apoptosis induction, inhibits the antiapoptotic factor BCL2 by a direct binding through its BH3-like domain. The mitochondrial AMBRA1-BCL2 complex is thus at the crossroad between autophagy and cell death and may represent a novel target in development of therapeutic approaches in clinical diseases.
a IRCCS Fondazione Santa Lucia , Rome , Italy.
Flavie
F
Strappazzon
a IRCCS Fondazione Santa Lucia , Rome , Italy.|b Department of Biology , University of Rome Tor Vergata , Rome , Italy.
Anthea
A
Di Rita
c Unit of Cell Stress and Survival, Danish Cancer Society Research Center , Copenhagen , Denmark.
Valentina
V
Cianfanelli
b Department of Biology , University of Rome Tor Vergata , Rome , Italy.
Melania
M
D'Orazio
a IRCCS Fondazione Santa Lucia , Rome , Italy.|b Department of Biology , University of Rome Tor Vergata , Rome , Italy.
Francesca
F
Nazio
d Department of Biological and Environmental Sciences and Technologies (DiSTeBA) , University of Salento, Lecce , Italy.|e National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome , Italy.
Gian Maria
GM
Fimia
a IRCCS Fondazione Santa Lucia , Rome , Italy.|b Department of Biology , University of Rome Tor Vergata , Rome , Italy.|c Unit of Cell Stress and Survival, Danish Cancer Society Research Center , Copenhagen , Denmark.
Francesco
F
Cecconi
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis; D002470:Cell Survival; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D008954:Models, Biological; D010539:Permeability; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019253:Proto-Oncogene Proteins c-bcl-2
AMBRA1; BCL2; BH3 domain; apoptosis; autophagy