USP10 strikes down β-catenin by dual-wielding deubiquitinase activity and phase separation potential
Abstract Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis and oncogenesis. Discovery of novel regulators holds great values in both basic and translational research. Through screening, we identified a deubiquitinase (DUB) USP10 as a novel and critical modulator of β-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination, and surprisingly, tethers Axin1 and β-catenin physically while promoting phase separation for β-catenin suppression regardless of its enzymatic activity. Functionally, USP10 prominently regulates embryonic development and intestinal homeostasis by antagonizing β-catenin via DUB activity. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical binding compensation and phase separation promotion and correlates with Wnt/β-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against β-catenin and unearthed a novel enzyme-dependent and -independent “dual-regulating” mechanism by which USP10 utilizes parallelly and context-dependently. USP10 inhibitor was suggested in treating certain Wnt-related diseases..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 23. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Yinuo [VerfasserIn] |
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| doi: |
10.1101/2022.10.31.514466 |
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| PPN (Katalog-ID): |
XBI037759566 |
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| 520 | |a Abstract Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis and oncogenesis. Discovery of novel regulators holds great values in both basic and translational research. Through screening, we identified a deubiquitinase (DUB) USP10 as a novel and critical modulator of β-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination, and surprisingly, tethers Axin1 and β-catenin physically while promoting phase separation for β-catenin suppression regardless of its enzymatic activity. Functionally, USP10 prominently regulates embryonic development and intestinal homeostasis by antagonizing β-catenin via DUB activity. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical binding compensation and phase separation promotion and correlates with Wnt/β-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against β-catenin and unearthed a novel enzyme-dependent and -independent “dual-regulating” mechanism by which USP10 utilizes parallelly and context-dependently. USP10 inhibitor was suggested in treating certain Wnt-related diseases. | ||
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| 700 | 1 | |a Mao, Aihua |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jingwei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Pengjie |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Shaoqin |e verfasserin |4 aut | |
| 700 | 1 | |a Tong, Tong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zexu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Haijiao |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Lanjing |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jiahui |e verfasserin |4 aut | |
| 700 | 1 | |a Pang, Zhongqiu |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Fukang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xinjun |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Maorong |e verfasserin |4 aut | |
| 700 | 1 | |a He, Xi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xi |e verfasserin |4 aut | |
| 700 | 1 | |a Fei, Teng |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Bi-Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Daming |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Liu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qiang |e verfasserin |0 (orcid)0000-0002-8735-8771 |4 aut | |
| 700 | 1 | |a Li, Yiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Sheng, Ren |e verfasserin |4 aut | |
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