An interconnected hierarchical model of cell death regulation by the BCL-2 family.
An interconnected hierarchical model of cell death regulation by the BCL-2 family.
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DOI：
10.1038/ncb3236
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发表时间：
2015-10
影响因子：
21.3
通讯作者：
Cheng EH
中科院分区：
文献类型：
--
作者：
Chen HC;Kanai M;Inoue-Yamauchi A;Tu HC;Huang Y;Ren D;Kim H;Takeda S;Reyna DE;Chan PM;Ganesan YT;Liao CP;Gavathiotis E;Hsieh JJ;Cheng EH
多结构域促凋亡BAX和巴克，一旦激活，透化线粒体触发细胞凋亡，而抗凋亡BCL-2成员保持线粒体的完整性。仅含BH 3的分子（BH 3 s）通过激活BAX-BAK或灭活抗凋亡成员来促进细胞凋亡。在这里，我们提出的生化和遗传证据表明，NOXA是一个真正的激活剂BH 3。在Bid−/−Bim−/−Puma−/−Noxa−/−和Bax−/−巴克−/−细胞中使用组合的功能获得和功能丧失方法，我们构建了一个相互关联的层次模型，该模型可以容纳并解释BCL-2成员之间复杂的相互作用如何决定细胞的生存与死亡。BID、BIM、BIA和NOXA直接诱导BAX-BAK的逐步双峰活化。BCL-2、BCL-XL和MCL-1分别通过螯合激活剂BH 3和BAX-BAK的“暴露于BH 3的”单体来抑制BAX-BAK激活的两种模式。此外，BAX和巴克的自激活可以通过BCL-2、BCL-XL和MCL-1的下调而独立于激活剂BH 3 s发生。我们的研究为靶向BCL-2家族治疗凋亡失调疾病奠定了基础。
Multidomain proapoptotic BAX and BAK, once activated, permeabilize mitochondria to trigger apoptosis, whereas antiapoptotic BCL-2 members preserve mitochondrial integrity. The BH3-only molecules (BH3s) promote apoptosis by either activating BAX-BAK or inactivating antiapoptotic members. Here, we present biochemical and genetic evidence that NOXA is a bona fide activator BH3. Using combinatorial gain-of-function and loss-of-function approaches in Bid−/−Bim−/−Puma−/−Noxa−/− and Bax−/−Bak−/− cells, we have constructed an interconnected hierarchical model that accommodates and explains how the intricate interplays between the BCL-2 members dictate cellular survival versus death. BID, BIM, PUMA and NOXA directly induce stepwise, bimodal activation of BAX-BAK. BCL-2, BCL-XL and MCL-1 inhibit both modes of BAX-BAK activation by sequestering activator BH3s and “BH3-exposed” monomers of BAX-BAK, respectively. Furthermore, autoactivation of BAX and BAK can occur independently of activator BH3s through downregulation of BCL-2, BCL-XL and MCL-1. Our studies lay a foundation on targeting the BCL-2 family for treating diseases with dysregulated apoptosis.