期刊
CELL DEATH AND DIFFERENTIATION
卷 19, 期 2, 页码 245-256出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2011.91
关键词
AIF; BAX; BID; calpains; necroptosis
资金
- Agence Nationale de la Recherche (ANR) [ANR-09-BLAN-0247]
- Association pour la Recherche sur le Cancer (ARC) [5104, 7987]
- Ligue Contre le Cancer
- Fondation de France
- Ecole Normale Superieure de Cachan (ENS-Cachan)
- Agence Nationale de la Recherche (ANR) [ANR-09-BLAN-0247] Funding Source: Agence Nationale de la Recherche (ANR)
Alkylating DNA-damage agents such as N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG) trigger necroptosis, a newly defined form of programmed cell death (PCD) managed by receptor interacting protein kinases. This caspase-independent mode of cell death involves the sequential activation of poly(ADP-ribose) polymerase-1 (PARP-1), calpains, BAX and AIF, which redistributes from mitochondria to the nucleus to promote chromatinolysis. We have previously demonstrated that the BAX-mediated mitochondrial release of AIF is a critical step in MNNG-mediated necroptosis. However, the mechanism regulating BAX activation in this PCD is poorly understood. Employing mouse embryonic knockout cells, we reveal that BID controls BAX activation in AIF-mediated necroptosis. Indeed, BID is a link between calpains and BAX in this mode of cell death. Therefore, even if PARP-1 and calpains are activated after MNNG treatment, BID genetic ablation abolishes both BAX activation and necroptosis. These PCD defects are reversed by reintroducing the BID-wt cDNA into the BID-/- cells. We also demonstrate that, after MNNG treatment, BID is directly processed into tBID by calpains. In this way, calpain non-cleavable BID proteins (BID-G70A or BID-Delta 68-71) are unable to promote BAX activation and necroptosis. Once processed, tBID localizes in the mitochondria of MNNG-treated cells, where it can facilitate BAX activation and PCD. Altogether, our data reveal that, as in caspase-dependent apoptosis, BH3-only proteins are key regulators of caspase-independent necroptosis. Cell Death and Differentiation (2012) 19, 245-256; doi:10.1038/cdd.2011.91; published online 8 July 2011
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