BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation - Archive ouverte HAL Access content directly
Journal Articles Cell Death and Differentiation Year : 2011

BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation

Santos A. Susin
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Lauriane Cabon
  • Function : Author
Patricia Galan-Malo
  • Function : Author
Aida Bouharrour
  • Function : Author
Laure Delavallee
  • Function : Author
Hans K Lorenzo
  • Function : Author
Atan Gross
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Alkylating DNA damage agents such as MNNG trigger necroptosis, a newly defined form of programmed cell death (PCD) managed by RIP kinases. This caspase-independent mode of cell death involves the sequential activation of 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.
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hal-00657645 , version 1 (08-01-2012)



Santos A. Susin, Lauriane Cabon, Patricia Galan-Malo, Aida Bouharrour, Laure Delavallee, et al.. BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation. Cell Death and Differentiation, 2011, ⟨10.1038/cdd.2011.91⟩. ⟨hal-00657645⟩


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