<br>BID、BIM 和 PUMA 对于激活 BAX 和 BAK 依赖性细胞死亡程序至关重要,Science

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BID、BIM 和 PUMA 对于激活 BAX 和 BAK 依赖性细胞死亡程序至关重要
Science ( IF 44.7 ) Pub Date : 2010-12-02 , DOI: 10.1126/science.1190217
Decheng Ren ₁ , Ho-Chou Tu , Hyungjin Kim , Gary X Wang , Gregory R Bean , Osamu Takeuchi , John R Jeffers , Gerard P Zambetti , James J-D Hsieh , Emily H-Y Cheng

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致命三重奏蛋白质 BAX 和 BAK 充当关键决策点，通过控制线粒体外膜的通透性来调节细胞凋亡。已有证据表明 BAX 和 BAK 的两种激活机制：一种间接机制，促凋亡蛋白中和 BCL-2 及其相关蛋白的抗凋亡作用；或通过 BIM、BID 或 PUMA 直接激活 BAX 和 BAK。由于 BIM、BID 和 PUMA 的功能重叠，体内情况的分析变得复杂。任等人。（第 1390 页；参见 Martin 的《Perspective》）因此分析了缺乏 BIM、BID 和 PUMA 的三重基因敲除小鼠。小鼠发育过程中的细胞凋亡需要这些蛋白质之一的直接作用来激活 BAX 或 BAK，从而促进细胞死亡。促凋亡蛋白直接作用于线粒体“看门人”蛋白，在小鼠发育过程中启动凋亡事件。尽管蛋白质 BAX 和 BAK 是线粒体凋亡启动所必需的，但 BAX 和 BAK 如何被激活仍不清楚。我们提供的体内证据证明了蛋白质 BID、BIM 和 PUMA 在激活 BAX 和 BAK 中的重要作用。 Bid、Bim 和 Puma 三重基因敲除小鼠表现出与 Bax 和 Bak 缺陷相关的相同发育缺陷，包括持续性指间蹼和阴道闭锁。 Bid、Bim 和 Puma 的基因删除阻止了 BAX 和 BAK 的同源寡聚化，从而阻止了细胞色素 c 介导的半胱天冬酶激活，以响应神经元和 T 淋巴细胞中的不同死亡信号，尽管存在其他仅 BH3 分子。因此，许多形式的细胞凋亡需要 BID、BIM 或 PUMA 蛋白家族成员直接激活线粒体处的 BAX 和 BAK。

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BID, BIM, and PUMA Are Essential for Activation of the BAX- and BAK-Dependent Cell Death Program

Deadly Trio The proteins BAX and BAK act as a key decision point, regulating apoptosis by controlling the permeability of the mitochondrial outer membrane. Evidence has been presented for two mechanisms of activation of BAX and BAK: an indirect mechanism where proapoptotic proteins neutralize the antiapoptotic effects of the protein BCL-2 and its relatives; or direct activation of BAX and BAK by BIM, BID, or PUMA. Analysis of the situation in vivo is complicated by the overlapping function of BIM, BID, and PUMA. Ren et al. (p. 1390; see the Perspective by Martin) thus analyzed triple-knockout mice lacking BIM, BID, and PUMA. Apoptosis during mouse development required a direct effect of one of these proteins to activate BAX or BAK, thereby promoting cell death. Proapoptotic proteins act directly on mitochondrial “gatekeeper” proteins to initiate apoptotic events during mouse development. Although the proteins BAX and BAK are required for initiation of apoptosis at the mitochondria, how BAX and BAK are activated remains unsettled. We provide in vivo evidence demonstrating an essential role of the proteins BID, BIM, and PUMA in activating BAX and BAK. Bid, Bim, and Puma triple-knockout mice showed the same developmental defects that are associated with deficiency of Bax and Bak, including persistent interdigital webs and imperforate vaginas. Genetic deletion of Bid, Bim, and Puma prevented the homo-oligomerization of BAX and BAK, and thereby cytochrome c–mediated activation of caspases in response to diverse death signals in neurons and T lymphocytes, despite the presence of other BH3-only molecules. Thus, many forms of apoptosis require direct activation of BAX and BAK at the mitochondria by a member of the BID, BIM, or PUMA family of proteins.

更新日期：2010-12-02

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