BCL-2, BCL-XL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis
BCL-2, BCL-XL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis
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DOI：
10.1016/s1097-2765(01)00320-3
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发表时间：
2001-09-01
期刊：
影响因子：
16
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Cheng, EHYA;Wei, MC;Korsmeyer, SJ
细胞凋亡中的关键问题包括caspase与细胞器功能障碍的重要性，抗凋亡与促凋亡bcl2成员的优势，以及承诺发生在线粒体的上游或下游。在这里，我们展示了下游效应因子Apaf-1、Caspase-9或Caspase-3缺失的细胞只表现出对“BH3结构域”分子的瞬时保护，并因线粒体功能障碍而死于caspase非依赖性死亡。具有上游缺陷、缺乏“多结构域”BAX、BAK的细胞表现出对所有BH3结构域成员的长期耐药，包括BAD、BIM和NOXA。野生型和突变型bcl2、bclX-L的比较表明，这些抗凋亡剂将BH3结构域的分子隔离在稳定的线粒体复合体中，阻止bax、bak的激活。因此，在哺乳动物中，只有BH3结构域的分子激活多结构域促凋亡成员来触发线粒体途径，该途径既释放细胞色素c来激活caspase，又启动caspase非依赖性线粒体功能障碍。
Critical issues in apoptosis include the importance of caspases versus organelle dysfunction, dominance of anti- versus proapoptotic BCL-2 members, and whether commitment occurs upstream or downstream of mitochondria. Here, we show cells deficient for the downstream effectors Apaf-1, Caspase-9, or Caspase-3 display only transient protection from "BH3 domain-only" molecules and die a caspase-independent death by mitochondrial dysfunction. Cells with an upstream defect, lacking "multidomain" BAX, BAK demonstrate long-term resistance to all BH3 domain-only members, including BAD, BIM, and NOXA. Comparison of wild-type versus mutant BCL-2, BCL-X-L indicates these antiapoptotics sequester BH3 domain-only molecules in stable mitochondrial complexes, preventing the activation of BAX, BAK. Thus, in mammals, BH3 domain-only molecules activate multidomain proapoptotic members to trigger a mitochondrial pathway, which both releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction.