Luo Xu, O'Neill Katelyn L, Huang Kai
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Alaska Medical Center, Omaha, ME, 68198-7696, USA.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA.
F1000Res. 2020 Aug 6;9. doi: 10.12688/f1000research.25607.1. eCollection 2020.
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.
Bax和Bak是Bcl-2家族中功能相似的两种促凋亡蛋白，由于它们作为线粒体外膜通透性改变（MOMP）的效应器所必需的作用，而被认为是细胞凋亡的门户，MOMP是线粒体依赖性凋亡过程中的一个主要步骤。细胞如何将Bax/Bak从惰性分子转变为完全活跃且具有致死性的效应器，长期以来一直是一场主要争论的焦点，这场争论围绕着两种相互竞争但并非相互排斥的模型展开：直接激活和间接激活。经过二十多年的深入研究，现在人们普遍认为，为了启动细胞凋亡，一些仅含BH3结构域的蛋白（Bcl-2家族的一个亚类）会直接与Bax/Bak相互作用，触发它们的构象转变和激活。然而，最近一系列利用此前无法获得的CRISPR工程细胞系统的发现，对支撑这一共识的基本前提提出了挑战，并为一种新颖且出人意料的简单Bax/Bak激活模型提供了证据：膜（脂质）介导的自发模型。本综述将讨论这一新模型的证据、原理、意义及影响。
