WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase
WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase
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DOI：
10.1101/gad.1624008
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发表时间：
2008-04-01
影响因子：
10.5
通讯作者：
Xiong, Yue
中科院分区：
文献类型：
--
作者：
Hu, Jian;Zacharek, Sima;Xiong, Yue
脑硬化症（TSC）是一种常染色体显性遗传疾病，其特征是在各种器官中形成错构瘤，并由靶向TSC 1或TSC 2基因的突变引起。TSC 1和TSC 2蛋白形成功能上相互依赖的二聚体复合物。不同激酶对任一TSC亚基的磷酸化调节TSC的功能，并且代表将各种信号整合到集中的细胞生长途径中的主要机制。靶向TSC 1或TSC 2的大多数疾病相关突变导致蛋白质水平大幅下降，表明蛋白质周转在TSC调节中也起着关键作用。在这里，我们报告TSC 2蛋白结合FBW 5，DDB 1结合WD 40（DWD）蛋白，并被FBW 5招募到DDB 1-CUL 4-ROC 1 E3泛素连接酶。FBW 5或CUL 4A的过表达促进TSC 2蛋白降解，并且这被TSC 1的共表达废除。相反，FBW 5、DDB 1或CUL 4A/B的耗尽使TSC 2稳定。果蝇中的Ddb 1或Cul 4突变导致Gigas/TSC 2蛋白积累，并导致生长缺陷，这些缺陷可以通过Gigas/TSC 2减少而部分挽救。这些结果表明FBW 5 DDB 1-CUL 4-ROC 1是调节TSC 2蛋白稳定性和TSC复合物周转的E3泛素连接酶。
Tuberous sclerosis (TSC) is an autosomal dominant disease characterized by hamartoma formation in various organs and is caused by mutations targeting either the TSC1 or TSC2 genes. TSC1 and TSC2 proteins form a functionally interdependent dimeric complex. Phosphorylation of either TSC subunit by different kinases regulates the function of TSC and represents a major mechanism to integrate various signals into a centralized cell growth pathway. The majority of disease-associated mutations targeting either TSC1 or TSC2 results in a substantial decrease in protein level, suggesting that protein turnover also plays a critical role in TSC regulation. Here we report that TSC2 protein binds to FBW5, a DDB1-binding WD40 (DWD) protein, and is recruited by FBW5 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase. Overexpression of FBW5 or CUL4A promotes TSC2 protein degradation, and this is abrogated by the coexpression of TSC1. Conversely, depletion of FBW5, DDB1, or CUL4A/B stabilizes TSC2. Ddb1 or Cul4 mutations in Drosophila result in Gigas/TSC2 protein accumulation and cause growth defects that can be partially rescued by Gigas/Tsc2 reduction. These results indicate that FBW5 DDB1-CUL4-ROC1 is an E3 ubiquitin ligase regulating TSC2 protein stability and TSC complex turnover.