|
|||||
|
|
Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13 |
|
| Authors: | Liu Junli Xia Hongguang Kim Minsu Xu Lihua Li Ying Zhang Lihong Cai Yu Norberg Helin Vakifahmetoglu Zhang Tao Furuya Tsuyoshi Jin Minzhi Zhu Zhimin Wang Huanchen Yu Jia Li Yanxia Hao Yan Choi Augustine Ke Hengming Ma Dawei Yuan Junying |
| Institution: | 1 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China 2 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue Boston, MA 02115, USA 3 Department of Biophysics and Biochemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA 4 Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA |
| Abstract: | 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. |
| Keywords: | |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ | |