Cheng Qiao, Yuan Yukang, Li Lemin, Guo Tingting, Miao Ying, Ren Ying, Liu Jin, Feng Qian, Wang Xiaofang, Zhao Peng, Zuo Yibo, Qian Liping, Zhang Liting, Zheng Hui
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, Jiangsu Province 215123, China.
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, Jiangsu Province 215123, China.
Exp Cell Res. 2017 Jul 1;356(1):1-7. doi: 10.1016/j.yexcr.2017.05.011. Epub 2017 May 13.
Ubiquitin-mediated proteolysis regulates cellular levels of various proteins, and therefore plays important roles in controlling cell signaling and disease progression. The Skp1-Cul1-F-box ubiquitin ligase β-TrCP is recognized as an important negative regulator for numerous key signaling proteins. Recently, the deubiquitinases (DUBs) have turned out to be essential to regulate signaling pathways related to human diseases. However, whether β-TrCP is able to regulate the deubiquitinase family members remains largely unexplored. Here, we found that β-TrCP downregulated cellular levels of endogenous USP33. We also revealed that β-TrCP interacted with USP33 independently of the classic binding motif for β-TrCP, and mediated USP33 degradation via the ubiquitin proteasome pathway. Furthermore, we found that the WD40 motif of β-TrCP and 201-400 amino acid motif of USP33 are required for the interaction between β-TrCP and USP33. Consequently, β-TrCP attenuated USP33-mediated inhibition of cell proliferation and cell invasion. Taken together, our study clarified that the E3 ligase β-TrCP regulates cellular USP33 levels by the ubiquitin-proteasomal proteolysis.
泛素介导的蛋白水解作用调节多种蛋白质的细胞水平，因此在控制细胞信号传导和疾病进展中发挥重要作用。Skp1-Cul1-F-box泛素连接酶β-TrCP被认为是众多关键信号蛋白的重要负调节因子。最近，去泛素化酶（DUBs）已被证明对调节与人类疾病相关的信号通路至关重要。然而，β-TrCP是否能够调节去泛素化酶家族成员在很大程度上仍未得到探索。在此，我们发现β-TrCP下调内源性USP33的细胞水平。我们还揭示，β-TrCP独立于其经典结合基序与USP33相互作用，并通过泛素蛋白酶体途径介导USP33的降解。此外，我们发现β-TrCP的WD40基序和USP33的201-400氨基酸基序是β-TrCP与USP33相互作用所必需的。因此，β-TrCP减弱了USP33介导的对细胞增殖和细胞侵袭的抑制作用。综上所述，我们的研究阐明了E3连接酶β-TrCP通过泛素-蛋白酶体蛋白水解作用调节细胞USP33水平。
