Targeting BAX ubiquitin-binding sites reveals that BAX activation is essential for its ubiquitin-dependent degradation |
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Authors: | Rui Peng Jialin Zhu Shujin Deng Hui Shi Shutao Xu Hongjuan Wu Fangdong Zou |
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Affiliation: | College of Life Sciences, Sichuan University, Chengdu, Sichuan, China |
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Abstract: | 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. |
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Keywords: | activation apoptotic ability BAX ubiquitination |
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