Apoptotic mitochondrial poration by a growing list of pore-forming BCL-2 family proteins.
Apoptotic mitochondrial poration by a growing list of pore-forming BCL-2 family proteins.
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越来越多的成孔 BCL-2 家族蛋白导致线粒体穿孔凋亡。
DOI：
10.1002/bies.202200221
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发表时间：
2023-03
期刊：
影响因子：
4
通讯作者：
Moldoveanu, Tudor
中科院分区：
文献类型：
--
作者：
Moldoveanu, Tudor
关键词：
孔形成BCL-2家族蛋白是细胞凋亡启动中线粒体穿孔的效应子。两个非典型效应物-BOK和截短BID（tBID）-加入典型效应物巴克和BAX。基因敲除揭示了在没有效应子的情况下的发育表型，支持它们在体内的作用。在细胞凋亡过程中，效应物被激活，并从休眠单体改变形状为与线粒体缔合并透化线粒体的动态寡聚体。BID通过蛋白水解激活，BOK在E3连接酶gp 78对其降解的抑制下积累，而巴克和BAX通过仅BH 3引发剂、自激活和交叉激活进行直接激活。除了tBID，线粒体上的效应寡聚体在超分辨率显微镜图像中显示为弧形和环形。巴克和BAX的BH 3-沟内二聚体、tBID单体和未表征的BOK种类是凋亡孔的推定构建块。效应子与脂质和双分子层相互作用，但膜穿孔的机制仍然难以捉摸。我讨论效应介导的线粒体穿孔。成孔效应BCL-2家族蛋白巴克、BAX、BOK和tBID通过线粒体外膜透化（MOMP）启动细胞凋亡。它们被上游死亡刺激激活，导致其蛋白水解、蛋白质-蛋白质和蛋白质-脂质相互作用和合成，最终通过活性推定单体和二聚体采用凋亡孔的难以捉摸的寡聚体构象。
The pore-forming BCL-2 family proteins are effectors of mitochondrial poration in apoptosis initiation. Two atypical effectors—BOK and truncated BID (tBID)—join the canonical effectors BAK and BAX. Gene knockout revealed developmental phenotypes in the absence the effectors, supporting their roles in vivo. During apoptosis effectors are activated and change shape from dormant monomers to dynamic oligomers that associate with and permeabilize mitochondria. BID is activated by proteolysis, BOK accumulates on inhibition of its degradation by the E3 ligase gp78, while BAK and BAX undergo direct activation by BH3-only initiators, autoactivation, and crossactivation. Except tBID, effector oligomers on the mitochondria appear as arcs and rings in super-resolution microscopy images. The BH3-in-groove dimers of BAK and BAX, the tBID monomers, and uncharacterized BOK species are the putative building blocks of apoptotic pores. Effectors interact with lipids and bilayers but the mechanism of membrane poration remains elusive. I discuss effector-mediated mitochondrial poration. The pore-forming, effector BCL-2 family proteins BAK, BAX, BOK, and tBID initiate apoptosis through mitochondrial outer membrane permeabilization (MOMP). They are activated by upstream death stimuli leading to their proteolysis, protein-protein and protein-lipid interactions, and synthesis, ultimately adopting elusive oligomeric conformations of apoptotic pores via active putative monomers and dimers.
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