USP42 通过保护 ZNRF3/RNF43 免受 R-spondin 依赖性降解来抑制 Wnt 信号通路。
USP42 protects ZNRF3/RNF43 from R-spondin-dependent clearance and inhibits Wnt signalling.
机构信息
Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany.
Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
出版信息
EMBO Rep. 2021 May 5;22(5):e51415. doi: 10.15252/embr.202051415. Epub 2021 Mar 30.
The tumour suppressors RNF43 and ZNRF3 play a central role in development and tissue homeostasis by promoting the turnover of the Wnt receptors LRP6 and Frizzled (FZD). The stem cell growth factor R-spondin induces auto-ubiquitination and membrane clearance of ZNRF3/RNF43 to promote Wnt signalling. However, the deubiquitinase stabilising ZNRF3/RNF43 at the plasma membrane remains unknown. Here, we show that the USP42 antagonises R-spondin by protecting ZNRF3/RNF43 from ubiquitin-dependent clearance. USP42 binds to the Dishevelled interacting region (DIR) of ZNRF3 and stalls the R-spondin-LGR4-ZNRF3 ternary complex by deubiquitinating ZNRF3. Accordingly, USP42 increases the turnover of LRP6 and Frizzled (FZD) receptors and inhibits Wnt signalling. Furthermore, we show that USP42 functions as a roadblock for paracrine Wnt signalling in colon cancer cells and mouse small intestinal organoids. We provide new mechanistic insights into the regulation R-spondin and conclude that USP42 is crucial for ZNRF3/RNF43 stabilisation at the cell surface.
肿瘤抑制因子 RNF43 和 ZNRF3 通过促进 Wnt 受体 LRP6 和 Frizzled（FZD）的周转，在发育和组织稳态中发挥核心作用。干细胞生长因子 R-spondin 诱导 ZNRF3/RNF43 的自身泛素化和膜清除，以促进 Wnt 信号传导。然而，稳定 ZNRF3/RNF43 在质膜上的去泛素酶仍然未知。在这里，我们表明 USP42 通过保护 ZNRF3/RNF43 免受泛素依赖性清除来拮抗 R-spondin。USP42 结合到 ZNRF3 的 Dishevelled 相互作用区域（DIR），并通过去泛素化 ZNRF3 使 R-spondin-LGR4-ZNRF3 三元复合物停滞。因此，USP42 增加了 LRP6 和 Frizzled（FZD）受体的周转率，并抑制了 Wnt 信号传导。此外，我们表明 USP42 在结肠癌细胞和小鼠小肠类器官中作为旁分泌 Wnt 信号的路障发挥作用。我们为 R-spondin 的调节提供了新的机制见解，并得出结论，USP42 对于 ZNRF3/RNF43 在细胞表面的稳定至关重要。
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