USP10 strikes down 8-catenin by dual-wielding deubiquitinase activity and phase separation potential

作者：Wang, Yinuo; Mao, Aihua; Liu, Jingwei; Li, Pengjie; Zheng, Shaoqin; Tong, Tong; Li, Zexu; Zhang, Haijiao; Ma, Lanjing; Lin, Jiahui; Han, Qing; Qi, Fukang; Zhang, Xinjun; Chen, Maorong; He, Xi; Zhang, Xi; Fei, Teng; Liu, Bi-Feng; Gao, Daming; Cao, Liu^*; Wang, Qiang^*; Li, Yiwei^*; Sheng, Ren^*

来源：Cell Chemical Biology, 2023, 30(11): 1436-+.

DOI：10.1016/j.chembiol.2023.07.016

• NEGATIVE REGULATOR
• E3 LIGASE
• WNT
• AXIN
• DEGRADATION
• INHIBITION
• STABILITY
• TUMORS
• WTX

Wnt/8-catenin signaling is a conserved pathway crucially governing development, homeostasis, and onco-genesis. Discoveries of its regulators hold great values in both basic and translational research. Through screening, we identified a deubiquitinase, USP10, as a critical modulator of 8-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination. Surprisingly, USP10 physically tethers Axin1 and 8-catenin and promotes the phase separation for 8-catenin suppression regardless of the enzymatic activity. Function-wise, USP10 enzymatic activity prefer-ably regulates embryonic development and both the enzymatic activity and physical function jointly control intestinal homeostasis by antagonizing 8-catenin. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical promotion of phase separation and correlates with Wnt/8-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against 8-cat-enin and unearthed the enzyme-dependent and-independent "dual-regulating"mechanism. These two functions of USP10 work in parallel and are context dependent.

• 单位
  中国医科大学; 汕头大学; 中国科学院; 东北大学; 华中科技大学