Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.10.31.514466v1?rss=1

Authors: 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., Zhang, X., Fei, T., Liu, B., Gao, D., Cao, L., Wang, Q., Li, Y., Sheng, R.

Abstract:
Wnt/{beta}-catenin signaling is a conserved pathway crucially governing development, tissue homeostasis and oncogenesis in metazoan. Through screening, we identified a deubiquitinase (DUB) USP10 as a novel modulator of Wnt/{beta}-catenin signaling. Mechanistically, USP10 binds to Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination. And in parallel, USP10 tethers Axin1 and {beta}-catenin physically, via stabilizing the phase separation of Axin1 through its intrinsically-disordered regions, which is regardless of its enzymatic activity. Functionally, we show USP10 prominently regulates zebrafish embryonic development and murine intestinal homeostasis by antagonizing Wnt/{beta}-catenin signaling. Additionally in human colorectal cancer, USP10 substantially represses cancer growth and correlates with Wnt/{beta}-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes through repressing Wnt/{beta}-catenin signaling and unearthed a novel DUB-dependent and -independent dual-regulating mechanism by which USP10 utilizes in Wnt regulation context-dependently. Our study also suggested the potential of USP10 inhibitor in treating Wnt-related diseases.

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