The intestinal stem cell (ISC) marker LGR5 is a receptor for R-spondin (RSPO) that functions to potentiate Wnt signalling in the proliferating crypt. It has been recently shown that Wnt plays a priming role for ISC self-renewal by inducing RSPO receptor LGR5 expression. Despite its pivotal role in homeostasis, regeneration and cancer, little is known about the post-translational regulation of LGR5. Here, we show that the HECT-domain E3 ligases NEDD4 and NEDD4L are expressed in the crypt stem cell regions and regulate ISC priming by degrading LGR receptors. Loss of Nedd4 and Nedd4l enhances ISC proliferation, increases sensitivity to RSPO stimulation and accelerates tumour development in Apcmin mice with increased numbers of high-grade adenomas. Mechanistically, we find that both NEDD4 and NEDD4L negatively regulate Wnt/β-catenin signalling by targeting LGR5 receptor and DVL2 for proteasomal and lysosomal degradation. Our findings unveil the previously unreported post-translational control of LGR receptors via NEDD4/NEDD4L to regulate ISC priming. Inactivation of NEDD4 and NEDD4L increases Wnt activation and ISC numbers, which subsequently enhances tumour predisposition and progression.

中文翻译：

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NEDD4 和 NEDD4L 通过降解 LGR5 受体来调节 Wnt 信号传导和肠道干细胞启动。


肠干细胞 (ISC) 标记物 LGR5 是 R-spondin (RSPO) 的受体，其功能是增强增殖隐窝中的 Wnt 信号传导。最近的研究表明，Wnt 通过诱导 RSPO 受体 LGR5 表达，在 ISC 自我更新中发挥启动作用。尽管 LGR5 在体内平衡、再生和癌症中发挥着关键作用，但人们对 LGR5 的翻译后调控知之甚少。在这里，我们发现 HECT 结构域 E3 连接酶 NEDD4 和 NEDD4L 在隐窝干细胞区域表达，并通过降解 LGR 受体来调节 ISC 启动。 Nedd4 和 Nedd4l 的缺失会增强 ISC 增殖，增加对 RSPO 刺激的敏感性，并加速 Apcmin 小鼠肿瘤的发展，并增加高级腺瘤的数量。从机制上讲，我们发现 NEDD4 和 NEDD4L 均通过靶向 LGR5 受体和 DVL2 进行蛋白酶体和溶酶体降解来负向调节 Wnt/β-catenin 信号传导。我们的研究结果揭示了之前未报道的 LGR 受体通过 NEDD4/NEDD4L 的翻译后控制来调节 ISC 启动。 NEDD4 和 NEDD4L 失活会增加 Wnt 激活和 ISC 数量，从而增强肿瘤易感性和进展。