BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation
BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation
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DOI：
10.1038/cdd.2011.91
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发表时间：
2012-02-01
影响因子：
12.4
通讯作者：
Susin, S. A.
中科院分区：
文献类型：
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作者：
Cabon, L.;Galan-Malo, P.;Susin, S. A.
烷基化dna损伤剂如n -甲基-n '-硝基-n '-亚硝基胍（MNNG）引发坏死性坏死，这是一种由受体相互作用蛋白激酶管理的新定义的程序性细胞死亡（PCD）形式。这种不依赖于caspase的细胞死亡模式包括poly（adp -核糖）聚合酶-1 （PARP-1）、calpains、BAX和AIF的顺序激活，这些酶从线粒体重新分配到细胞核以促进染色质溶解。我们之前已经证明bax介导的线粒体释放AIF是mnng介导的坏死坏死的关键步骤。然而，在这种PCD中调节BAX激活的机制尚不清楚。利用小鼠胚胎敲除细胞，我们发现BID在aif介导的坏死性坏死中控制BAX的激活。事实上，在这种细胞死亡模式中，BID是calpain和BAX之间的联系。因此，即使在MNNG治疗后PARP-1和calpain被激活，BID基因消融也能消除BAX激活和坏死下垂。通过将BID-wt cDNA重新导入BID-/-细胞，这些PCD缺陷得以逆转。我们还证明，经过MNNG处理后，BID被calpain直接加工成tBID。因此，calpain不可切割的BID蛋白（BID- g70a或BID- delta 68-71）不能促进BAX激活和坏死坏死。一旦处理，tBID定位于mnng处理细胞的线粒体中，在那里它可以促进BAX的激活和PCD。总之，我们的数据显示，在caspase依赖性细胞凋亡中，仅bh3蛋白是caspase非依赖性坏死坏死的关键调节因子。细胞死亡与分化（2012）19,245-256；doi: 10.1038 / cdd.2011.91;2011年7月8日在线发布
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