USP10 strikes down Wnt/β-catenin signaling by dual-wielding deubiquitinase activity and phase transition potential

Wang, Y.; Mao, A.; Liu, J.; Li, P.; Zheng, S.; Tong, T.; Li, Z.; Zhang, H.; Ma, L.; Lin, J.; Pang, Z.; Han, Q.; Li, F.; Zhang, X.; Chen, M.; He, X.; Fei, T.; Liu, B.; Gao, D.; Cao, L.; Wang, Q.; Li, Y.; Sheng, R.

doi:10.1101/2022.10.31.514466

bioRxiv · 10.1101/2022.10.31.514466

USP10 strikes down Wnt/β-catenin signaling by dual-wielding deubiquitinase activity and phase transition potential

Wang, Y.·Mao, A.·Liu, J.·Li, P.·Zheng, S.·Tong, T.·Li, Z.·Zhang, H.·Ma, L.·Lin, J.·Pang, Z.·Han, Q.·Li, F.·Zhang, X.·Chen, M.·He, X.·Fei, T.·Liu, B.·Gao, D.·Cao, L.·Wang, Q.·Li, Y.·Sheng, R.

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Abstract

Wnt/{beta}-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 {beta}-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination, and surprisingly, tethers Axin1 and {beta}-catenin physically while promoting phase separation for {beta}-catenin suppression regardless of its enzymatic activity. Functionally, USP10 prominently regulates embryonic development and intestinal homeostasis by antagonizing {beta}-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/{beta}-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against {beta}-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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Wang, Y., Mao, A., Liu, J., Li, P., Zheng, S., Tong, T., Li, Z., Zhang, H., Ma, L., Lin, J., Pang, Z., Han, Q., Li, F., Zhang, X., Chen, M., He, X., Fei, T., Liu, B., Gao, D., Cao, L., Wang, Q., Li, Y., Sheng, R.. 2022-11-01. USP10 strikes down Wnt/β-catenin signaling by dual-wielding deubiquitinase activity and phase transition potential. https://doi.org/10.1101/2022.10.31.514466

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