Beclin1 Controls the Levels of p53 by Regulating the Deubiquitination Activity of USP10 and USP13

被引:680
作者
Liu, Junli [1 ]
Xia, Hongguang [1 ]
Kim, Minsu [2 ]
Xu, Lihua [1 ]
Li, Ying [1 ,2 ]
Zhang, Lihong [1 ]
Cai, Yu [1 ]
Norberg, Helin Vakifahmetoglu [2 ]
Zhang, Tao [1 ]
Furuya, Tsuyoshi [2 ]
Jin, Minzhi [1 ]
Zhu, Zhimin [2 ]
Wang, Huanchen [3 ]
Yu, Jia [1 ]
Li, Yanxia [1 ]
Hao, Yan [1 ]
Choi, Augustine [4 ]
Ke, Hengming [3 ]
Ma, Dawei [1 ]
Yuan, Junying [2 ]
机构
[1] Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China
[2] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[3] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA
[4] Brigham & Womens Hosp, Boston, MA 02115 USA
基金
中国国家自然科学基金;
关键词
TUMOR-SUPPRESSOR; AUTOPHAGY GENE; TUMORIGENESIS; PROTEINS; INHIBITION; COMPLEXES; RUBICON; SCREEN; ATG14L; VPS34;
D O I
10.1016/j.cell.2011.08.037
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Autophagy is an important intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles. We report a potent small molecule inhibitor of autophagy named "spautin-1" for specific and potent autophagy inhibitor-1. Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Beclin1 is a tumor suppressor and frequently monoallelically lost in human cancers. Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. Our study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.
引用
收藏
页码:223 / 234
页数:12
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