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

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1270-1281
Number of pages12
JournalNature Cell Biology
Volume17
Issue number10
DOIs
StatePublished - Oct 3 2015

ASJC Scopus subject areas

  • Cell Biology

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    Chen, H. C., Kanai, M., Inoue-Yamauchi, A., Tu, H. C., Huang, Y., Ren, D., Kim, H., Takeda, S., Reyna, D. E., Chan, P. M., Ganesan, Y. T., Liao, C. P., Gavathiotis, E., Hsieh, J. J., & Cheng, E. H. (2015). An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nature Cell Biology, 17(10), 1270-1281. https://doi.org/10.1038/ncb3236