An interconnected hierarchical model of cell death regulation by the BCL-2 family

Hui Chen Chen, Masayuki Kanai, Akane Inoue-Yamauchi, Ho Chou Tu, Yafen Huang, Decheng Ren, Hyungjin Kim, Shugaku Takeda, Denis E. Reyna, Po M. Chan, Yogesh Tengarai Ganesan, Chung Ping Liao, Evripidis Gavathiotis, James J. Hsieh, Emily H. Cheng

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174 引文 斯高帕斯(Scopus)

摘要

Multidomain pro-apoptotic BAX and BAK, once activated, permeabilize mitochondria to trigger apoptosis, whereas anti-apoptotic BCL-2 members preserve mitochondrial integrity. The BH3-only molecules (BH3s) promote apoptosis by either activating BAX-BAK or inactivating anti-apoptotic members. Here, we present biochemical and genetic evidence that NOXA is a bona fide activator BH3. Using combinatorial gain-of-function and loss-of-function approaches in Bid -/- Bim -/- Puma -/- Noxa -/- and Bax -/- Bak -/- cells, we have constructed an interconnected hierarchical model that accommodates and explains how the intricate interplays between the BCL-2 members dictate cellular survival versus death. BID, BIM, PUMA and NOXA directly induce stepwise, bimodal activation of BAX-BAK. BCL-2, BCL-X L and MCL-1 inhibit both modes of BAX-BAK activation by sequestering activator BH3s and 'BH3-exposed' monomers of BAX-BAK, respectively. Furthermore, autoactivation of BAX and BAK can occur independently of activator BH3s through downregulation of BCL-2, BCL-X L and MCL-1. Our studies lay a foundation for targeting the BCL-2 family for treating diseases with dysregulated apoptosis.
原文英語
頁(從 - 到)1270-1281
頁數12
期刊Nature Cell Biology
17
發行號10
DOIs
出版狀態已發佈 - 10月 3 2015
對外發佈

ASJC Scopus subject areas

  • 細胞生物學

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