标题:BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis
作者:Huang, Kai; O'Neill, Katelyn L.; Li, Jian; Zhou, Wei; Han, Na; Pang, Xiaming; Wu, Wei; Struble, Lucas; Borgstahl, Gloria; Liu, Zhaor 更多
作者机构:[Huang, Kai; O'Neill, Katelyn L.; Li, Jian; Zhou, Wei; Han, Na; Pang, Xiaming; Wu, Wei; Struble, Lucas; Borgstahl, Gloria; Liu, Zhaorui; Zhang, Liqian 更多
通讯作者:Luo, X;Luo, X
通讯作者地址:[Luo, X]Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA;[Luo, X]Univ Nebraska Med Ctr, D 更多
来源:CELL RESEARCH
出版年:2019
卷:29
期:11
页码:942-952
DOI:10.1038/s41422-019-0231-y
摘要:It has been widely accepted that mitochondria-dependent apoptosis initiates when select BH3-only proteins (BID, BIM, etc.) directly engage and allosterically activate effector proteins BAX/BAK. Here, through reconstitution of cells lacking all eight pro-apoptotic BH3-only proteins, we demonstrate that all BH3-only proteins primarily target the anti-apoptotic BCL-2 proteins BCL-xL/MCL-1, whose simultaneous suppression enables membrane-mediated spontaneous activation of BAX/BAK. BH3-only proteins' apoptotic activities correlate with affinities for BCL-xL/MCL-1 instead of abilities to directly activate BAX/BAK. Further, BID and BIM do not distinguish BAX from BAK or accelerate BAX/BAK activation following inactivation of BCL-xL/MCL-1. Remarkably, death ligandinduced apoptosis in cells lacking BH3-only proteins and MCL-1 is fully restored by BID mutants capable of neutralizing BCL-xL, but not direct activation of BAX/BAK. Taken together, our findings provide a "Membrane-mediated Permissive" model, in which the BH3-only proteins only indirectly activate BAX/BAK by neutralizing the anti-apoptotic BCL-2 proteins, and thus allowing BAX/BAK to undergo unimpeded, spontaneous activation in the mitochondrial outer membrane milieu, leading to apoptosis initiation.
收录类别:SCOPUS;SCIE
资源类型:期刊论文
原文链接:https://www.scopus.com/inward/record.uri?eid=2-s2.0-85073945686&doi=10.1038%2fs41422-019-0231-y&partnerID=40&md5=2465e64d862a9de37cff44118059a237
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