Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane.
Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane.
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DOI：
10.1101/gad.276725.115
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发表时间：
2016-04-15
影响因子：
10.5
通讯作者：
Luo X
中科院分区：
文献类型：
--
作者：
O'Neill KL;Huang K;Zhang J;Chen Y;Luo X
在这项研究中，奥尼尔等人使用基因组编辑来产生缺乏所有八种促凋亡BH 3-only蛋白（OctaKO）的细胞和缺乏整个Bcl-2家族（Bcl-2 allKO）的细胞。他们的研究结果表明，线粒体外膜（OMM），而不是BH 3-only蛋白或p53/Rb，是Bax/巴克的直接激活剂后，BH 3-only介导的抗凋亡Bcl-2蛋白的中和。Bax/巴克激活的机制仍然是细胞凋亡信号转导的中心问题。虽然已经确定所有促凋亡Bcl-2同源性3（BH 3）-唯一蛋白结合并中和抗凋亡Bcl-2家族蛋白，但是这种中和如何导致Bax/巴克活化一直在积极争论。在这里，基因组编辑用于产生缺乏所有八种促凋亡BH 3-only蛋白（OctaKO）和缺乏整个Bcl-2家族（Bcl-2 allKO）的细胞。虽然OctaKO细胞对测试的大多数凋亡刺激具有抗性，但是当两种抗凋亡Bcl-2蛋白Bcl-xL和Mcl-1被灭活或消除时，它们有效地经历Bax/Bak-dependent和p53/Rb-independent凋亡。引人注目的是，当在Bcl-2 allKO细胞中表达时，Bax和巴克都通过它们各自的螺旋9自发地与线粒体外膜（OMM）结合，并且这种结合触发了它们的同源寡聚化/活化。总之，这些结果强烈地表明，OMM，而不是仅BH 3蛋白或p53/Rb，是在仅BH 3介导的抗凋亡Bcl-2蛋白的中和之后长期寻求的Bax/巴克的直接激活剂。
In this study, O'Neill et al. used genome editing to generate cells deficient for all eight proapoptotic BH3-only proteins (OctaKO) and cells that lack the entire Bcl-2 family (Bcl-2 allKO). Their findings suggest that the outer mitochondrial membrane (OMM), not BH3-only proteins or p53/Rb, is the direct activator of Bax/Bak following BH3-only-mediated neutralization of anti-apoptotic Bcl-2 proteins. The mechanism of Bax/Bak activation remains a central question in mitochondria-dependent apoptotic signaling. While it is established that all proapoptotic Bcl-2 homology 3 (BH3)-only proteins bind and neutralize the anti-apoptotic Bcl-2 family proteins, how this neutralization leads to Bax/Bak activation has been actively debated. Here, genome editing was used to generate cells deficient for all eight proapoptotic BH3-only proteins (OctaKO) and those that lack the entire Bcl-2 family (Bcl-2 allKO). Although the OctaKO cells were resistant to most apoptotic stimuli tested, they underwent Bax/Bak-dependent and p53/Rb-independent apoptosis efficiently when both Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins, were inactivated or eliminated. Strikingly, when expressed in the Bcl-2 allKO cells, both Bax and Bak spontaneously associated with the outer mitochondrial membrane (OMM) through their respective helix 9, and this association triggered their homo-oligomerization/activation. Together, these results strongly suggest that the OMM, not BH3-only proteins or p53/Rb, is the long-sought-after direct activator of Bax/Bak following BH3-only-mediated neutralization of anti-apoptotic Bcl-2 proteins.