CRL4B-RBBP7 targets HUWE1 for ubiquitination and proteasomal degradation
CRL4B-RBBP7 targets HUWE1 for ubiquitination and proteasomal degradation
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CRL4B-RBBP7 针对 HUWE1 进行泛素化和蛋白酶体降解
DOI：
10.1016/j.bbrc.2018.05.008
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Genze Shao
中科院分区：
文献类型：
--
作者：
Fei Liu;Li Cao;Ting Zhang;Fen Chang;Yongjie Xu;Qin Li;Jingcheng Deng;Li Li;Genze Shao
E3泛素连接酶HUWE 1/Mule/ARF-BP 1在DNA损伤修复和细胞凋亡等多种生物学过程中发挥重要作用。我们以前的研究表明，在响应DNA损伤HUWE 1下调CUL 4 B介导的泛素化和随后的蛋白酶体降解，和CUL 4 B介导的HUWE 1的调节是重要的DNA损伤后的细胞存活。CUL 4 B是CUL 4 B环连接酶复合物的核心组分，该复合物含有ROC 1、DDB 1和DDB 1-Cullin相关因子（DCAF），后者是DDB 1结合的WD 40衔接子，对于底物识别和募集至关重要。然而，CRL 4 B中介导HUWE 1降解的DCAF的身份仍然难以捉摸。在这里，我们报告RBBP 7是CRL 4 B复合物中的DCAF，将DDB 1-CUL 4 B-ROC 1桥接到HUWE 1。HUWE 1加载到E3泛素连接酶复合物导致其多聚泛素化，并因此导致其蛋白酶体介导的降解。RBBP 7的过表达促进了HUWE 1蛋白的降解，而RBBP 7的缺失稳定了HUWE 1，因此加速了HUWE 1的两种底物MCL-1和BRCA 1的降解，这两种底物在细胞凋亡和DNA损伤修复中至关重要。综上所述，这些数据揭示了CRL 4 BRBBP 7是负责HUWE 1蛋白酶体降解的E3连接酶，并进一步提供了通过靶向HUWE 1和CUL 4 B E3连接酶复合物进行癌症治疗的潜在策略。
The E3 ubiquitin ligase HUWE1/Mule/ARF-BP1 plays an important role in diverse biological processes including DNA damage repair and apoptosis. Our previous study has shown that in response to DNA damage HUWE1 was downregulated in CUL4B-mediated ubiquitination and subsequent proteasomal degradation, and CUL4B-mediated regulation of HUWE1 was important for cell survival upon DNA damage. CUL4B is a core component of the CUL4B Ring ligase complexes containing ROC1, DDB1 and a DDB1-Cullin Associated Factors (DCAFs), the latter of which are DDB1-binding WD40 adaptors critical for substrate recognition and recruitment. However, the identity of DCAF in CRL4B that mediates degradation of HUWE1 remains elusive. Here we report that RBBP7 is the DCAF in the CRL4B complex bridging the DDB1-CUL4B-ROC1 to HUWE1. Loading of HUWE1 to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome mediated degradation. Overexpression of RBBP7 promoted HUWE1 protein degradation, while depletion of RBBP7 stabilized HUWE1, and hence accelerated the degradation of MCL-1 and BRCA1, two substrates of HUWE1 that are critical in apoptosis and DNA damage repair. Taken together, these data reveal CRL4BRBBP7is the E3 ligase responsible for the proteasomal degradation of HUWE1, and further provide a potential strategy for cancer therapy by targeting HUWE1 and the CUL4B E3 ligase complex.