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

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

doi:10.1016/j.chembiol.2023.07.016

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

Cell Chem Biol. 2023 Nov 16;30(11):1436-1452.e10. doi: 10.1016/j.chembiol.2023.07.016. Epub 2023 Aug 22.

Authors

Yinuo Wang¹, Aihua Mao², Jingwei Liu³, Pengjie Li⁴, Shaoqin Zheng¹, Tong Tong¹, Zexu Li¹, Haijiao Zhang¹, Lanjing Ma¹, Jiahui Lin¹, Zhongqiu Pang¹, Qing Han¹, Fukang Qi⁴, Xinjun Zhang⁵, Maorong Chen⁶, Xi He⁶, Xi Zhang⁷, Teng Fei¹, Bi-Feng Liu⁴, Daming Gao⁸, Liu Cao⁹, Qiang Wang¹⁰, Yiwei Li¹¹, Ren Sheng¹²

Affiliations

¹ College of Life and Health Science, Northeastern University, Shenyang 110819, China.
² Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, Guangdong 515063, China.
³ College of Basic Medical Science, China Medical University, Shenyang 110122, China.
⁴ Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics - Hubei Bioinformatics and Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
⁵ Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
⁶ F.M Kirby Neurobiology Center, Boston Children's Hospital, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
⁷ College of Sciences, Northeastern University, Shenyang 110004, China.
⁸ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
⁹ College of Basic Medical Science, China Medical University, Shenyang 110122, China. Electronic address: lcao@cmu.edu.cn.
¹⁰ Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou 510006, China. Electronic address: qiangwang@scut.edu.cn.
¹¹ Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics - Hubei Bioinformatics and Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China. Electronic address: yiweili@hust.edu.cn.
¹² College of Life and Health Science, Northeastern University, Shenyang 110819, China. Electronic address: shengren@mail.neu.edu.cn.

PMID: 37611590
DOI: 10.1016/j.chembiol.2023.07.016

Abstract

Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis, and oncogenesis. 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 β-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination. Surprisingly, USP10 physically tethers Axin1 and β-catenin and promotes the phase separation for β-catenin suppression regardless of the enzymatic activity. Function-wise, USP10 enzymatic activity preferably regulates embryonic development and both the enzymatic activity and physical function jointly control intestinal homeostasis by antagonizing β-catenin. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical promotion of phase separation and correlates with Wnt/β-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against β-catenin and unearthed the enzyme-dependent and -independent "dual-regulating" mechanism. These two functions of USP10 work in parallel and are context dependent.

Keywords: USP10; Wnt/β-catenin; phase separation; ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Deubiquitinating Enzymes / metabolism
Wnt Signaling Pathway*
beta Catenin* / metabolism

Substances

beta Catenin
Deubiquitinating Enzymes