BH3 Domains other than Bim and Bid Can Directly Activate Bax/Bak
BH3 Domains other than Bim and Bid Can Directly Activate Bax/Bak
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DOI：
10.1074/jbc.m110.167148
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发表时间：
2011-01-07
影响因子：
4.8
通讯作者：
Kuwana, Tomomi
中科院分区：
文献类型：
--
作者：
Du, Han;Wolf, Jacob;Kuwana, Tomomi
Bcl-2家族蛋白调节细胞凋亡的关键步骤，即线粒体外膜通透性（MOMP）。Bcl-2家族的一个亚群成员，被称为BH3-only蛋白，激活促凋亡效应因子（Bax和Bak）来启动MOMP。它们通过中和促生存Bcl-2蛋白和/或直接激活Bax/Bak来实现。据报道，Bim和Bid是直接激活者；然而，这里我们发现除了Bim和Bid之外，BH3肽表现出不同程度的直接激活效应Bax或Bak，包括Bmf和Noxa BH3。在缺乏有效的直接激活剂（如Bim和Bid）的情况下，我们发现了新的直接激活剂BH3配体，即使在Bcl-xL-和mcl -1型抗凋亡蛋白被抑制的情况下，也能诱导效应介导的细胞色素c释放和脂质体渗透。在缺乏Bim和Bid的情况下，这些较弱的直接激活剂BH3肽引起MOMP的能力与相应全长蛋白诱导凋亡的能力相关。我们提出，在某些情况下，除了Bim和Bid之外，仅bh3蛋白的直接激活可能会显著促进MOMP和细胞凋亡。
Bcl-2 family proteins regulate a critical step in apoptosis referred to as mitochondrial outer membrane permeabilization (MOMP). Members of a subgroup of the Bcl-2 family, known as the BH3-only proteins, activate pro-apoptotic effectors (Bax and Bak) to initiate MOMP. They do so by neutralizing pro-survival Bcl-2 proteins and/or directly activating Bax/Bak. Bim and Bid are reported to be direct activators; however, here we show that BH3 peptides other than Bim and Bid exhibited various degrees of direct activation of the effector Bax or Bak, including Bmf and Noxa BH3s. In the absence of potent direct activators, such as Bim and Bid, we unmasked novel direct activator BH3 ligands capable of inducing effector-mediated cytochrome c release and liposome permeabilization, even when both Bcl-xL- and Mcl-1-type anti-apoptotic proteins were inhibited. The ability of these weaker direct activator BH3 peptides to cause MOMP correlated with that of the corresponding full-length proteins to induce apoptosis in the absence of Bim and Bid. We propose that, in certain contexts, direct activation by BH3-only proteins other than Bim and Bid may significantly contribute to MOMP and apoptosis.