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

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

来源：Nature Cell Biology, 2015, 17(10): 1270-+.

DOI：10.1038/ncb3236

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.

• 出版日期2015-10