ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner
ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner
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DOI：
10.1038/nature11019
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发表时间：
2012-05-10
期刊：
影响因子：
64.8
通讯作者：
Cong, Feng
中科院分区：
文献类型：
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作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
R-Respondin蛋白强烈增强Wnt信号，并作为干细胞生长因子发挥作用。尽管具有生物学和治疗意义，但R-Respondin作用的分子机制尚不清楚。在这里，我们证明了细胞表面跨膜E3泛素连接酶锌和环指3(ZNRF3)及其同源环指43(RNF43)是Wnt信号的负反馈调节因子。ZNRF3与Wnt受体复合体相关，通过促进FrizzledLRP6的周转来抑制Wnt信号转导。在体内，抑制ZNRF3可增强Wnt/β-catenin信号转导并干扰Wnt/Plane细胞极性信号转导。值得注意的是，R-pondin通过增加Wnt受体的膜水平来模拟ZNRF3的抑制。从机制上讲，R-Respondin与ZNRF3的胞外区相互作用，导致ZNRF3与LGR4的结合，从而导致ZNRF3的膜清除。这些数据表明，R-Respondin通过抑制ZNRF3来增强Wnt信号。我们的研究为Wnt受体周转的调节提供了新的机制见解，并揭示了ZNRF3是治疗探索的一个容易处理的靶点。
R-spondin proteins strongly potentiate Wnt signalling and function as stem-cell growth factors. Despite the biological and therapeutic significance, the molecular mechanism of R-spondin action remains unclear. Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. Inhibition of ZNRF3 enhances Wnt/beta-catenin signalling and disrupts Wnt/ planar cell polarity signalling in vivo. Notably, R-spondin mimics ZNRF3 inhibition by increasing the membrane level of Wnt receptors. Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3. Our study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration.