The third model of Bax/Bak activation: a Bcl-2 family feud finally resolved?
The third model of Bax/Bak activation: a Bcl-2 family feud finally resolved?
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DOI：
10.12688/f1000research.25607.1
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发表时间：
2020-01-01
期刊：
影响因子：
--
通讯作者：
Huang, Kai
中科院分区：
文献类型：
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作者：
Luo, Xu;O'Neill, Katelyn L;Huang, Kai
Bax和巴克是Bcl-2家族的两种功能相似的促凋亡蛋白，由于它们作为线粒体外膜透化（MOMP）效应物的必要作用，被称为细胞凋亡的门户，MOMP是Bcl-2依赖性细胞凋亡过程中的主要步骤。细胞如何将Bax/巴克从惰性分子转变为完全活跃和致命的效应物的机制一直是围绕两种竞争但不相互排斥的模型的主要争论的焦点：直接激活和间接激活。经过20多年的深入研究，现已广泛接受，为了启动细胞凋亡，Bcl-2家族的一个亚类的一些仅BH 3蛋白直接接合Bax/巴克以触发它们的构象转化和激活。然而，最近的一系列发现，使用以前不可用的CRISPR工程细胞系统，挑战了支持共识的基本前提，并为Bax/巴克激活的新的和令人惊讶的简单模型提供了证据：膜（脂质）介导的自发模型。本文将讨论这一新模式的证据，理论基础，意义和影响。
Bax and Bak, two functionally similar, pro-apoptotic proteins of the Bcl-2 family, are known as the gateway to apoptosis because of their requisite roles as effectors of mitochondrial outer membrane permeabilization (MOMP), a major step during mitochondria-dependent apoptosis. The mechanism of how cells turn Bax/Bak from inert molecules into fully active and lethal effectors had long been the focal point of a major debate centered around two competing, but not mutually exclusive, models: direct activation and indirect activation. After intensive research efforts for over two decades, it is now widely accepted that to initiate apoptosis, some of the BH3-only proteins, a subclass of the Bcl-2 family, directly engage Bax/Bak to trigger their conformational transformation and activation. However, a series of recent discoveries, using previously unavailable CRISPR-engineered cell systems, challenge the basic premise that undergirds the consensus and provide evidence for a novel and surprisingly simple model of Bax/Bak activation: the membrane (lipids)-mediated spontaneous model. This review will discuss the evidence, rationale, significance, and implications of this new model.