title: BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation.
abstract: 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-Δ68-71) 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.
authors: INSERM U872, Mort Cellulaire Programmée et Physiopathologie des Cellules Tumorales, Equipe 19, Centre de Recherche des Cordeliers, Paris, France.
authors: L
authors: L
authors: Cabon
authors: P
authors: P
authors: Galán-Malo
authors: A
authors: A
authors: Bouharrour
authors: L
authors: L
authors: Delavallée
authors: M-N
authors: MN
authors: Brunelle-Navas
authors: H K
authors: HK
authors: Lorenzo
authors: A
authors: A
authors: Gross
authors: S A
authors: SA
authors: Susin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002154:Calpain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009336:Necrosis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014161:Transduction, Genetic; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D008769:Methylnitronitrosoguanidine; D011065:Poly(ADP-ribose) Polymerases; D002154:Calpain; D020169:Caspases