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Targeting BAX ubiquitin‐binding sites reveals that BAX activation is essential for its ubiquitin‐dependent degradation
Author(s) -
Peng Rui,
Zhu Jialin,
Deng Shujin,
Shi Hui,
Xu Shutao,
Wu Hongjuan,
Zou Fangdong
Publication year - 2020
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.29505
Subject(s) - ubiquitin , ubiquitin ligase , parkin , apoptosis , proteasome , microbiology and biotechnology , mutant , bcl 2 associated x protein , chemistry , biology , biochemistry , programmed cell death , gene , caspase 3 , medicine , parkinson's disease , disease , pathology
BAX is an important proapoptotic protein of the BCL‐2 family, and its stability is essential for the regulation of the mitochondrial apoptotic pathway. A previous study revealed that BAX could undergo degradation through the ubiquitin‐proteasome pathway. In this study, we identified two lysine sites, K21 and K123, that were critical ubiquitin‐binding sites in BAX. Mutation of these two sites prolonged the half‐life of BAX and also affected its proapoptotic ability. Intriguingly, we found that ABT‐737, a BCL‐2 inhibitor, significantly enhanced TRAIL‐induced BAX degradation in HCT116 cells and increased TRAIL‐induced apoptosis in the HCT116 only with the BAX K21R/K123R mutant, not other BAX mutants. In addition, overexpression of PARKIN, an E3 ubiquitin ligase targeting BAX, dramatically decreased BAX protein level when only treated with ABT‐737 in HCT116 cells. Therefore, we speculated that BAX activation is essential for its ubiquitin‐dependent degradation.