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, tissue homeostasis and oncogenesis in metazoan. Through screening, we identified a deubiquitinase (DUB) USP10 as a novel modulator of Wnt/β-catenin signaling. Mechanistically, USP10 binds to Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination. And in parallel, USP10 tethers Axin1 and β-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/β-catenin signaling. Additionally in human colorectal cancer, USP10 substantially represses cancer growth and correlates with Wnt/β-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes through repressing Wnt/β-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.

The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/β‐catenin signaling in cancer

“…We found that the use of AMPK agonists significantly reduced of TOPFlash reporter intensity under Wnt3a conditioned medium only when USP10 was present (Fig. 1G) [17]. We mutated Ser76 on USP10 to mimic the presence (S76D) and absence (S76A) of AMPK phosphorylation.…”

“…Based on our recent report of the physical role of USP10 [17], we tested whether AMPK phosphorylation could alter the physical property of USP10. Interestingly, we found that USP10‐S76A showed minimal binding toward β‐catenin, and the phosphorylation‐mimic mutant, S76D, behaved oppositely (Fig.…”

“…4B-E). We thus propose that the LKB1/AMPK axis suppresses CRC growth via two approaches: one, through classical antagonization of cell metabolism such as counteracting mTORC1 activity [3]; two, through cancer cell self-renewal inhibition and cell cycle arrestment by dampening Wnt/β-catenin activity via the invigoration of USP10 and Axin1 [17] (Fig. 4F).…”

“…USP10 is a conserved, versatile, and well‐studied deubiquitinase that has been shown to deubiquitinate multiple substrates [13–16]. Recently, we have discovered that USP10 can stabilize Axin1 via deubiquitination [17]. And more importantly, we have shown that USP10 participates in the phase separation of β‐catenin destruction complex independent of its enzymatic activity [17].…”

“…Recently, we have discovered that USP10 can stabilize Axin1 via deubiquitination [17]. And more importantly, we have shown that USP10 participates in the phase separation of β‐catenin destruction complex independent of its enzymatic activity [17]. In terms of regulation, it was reported that the activated AMPK phosphorylates USP10 on Ser76, which enhances the activity of USP10.…”