The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation.
The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation.
复制标题
SIAH E3 泛素连接酶通过介导 Wnt 诱导的轴蛋白降解来促进 Wnt/β-连环蛋白信号传导。
DOI：
10.1101/gad.300053.117
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发表时间：
2017-05-01
影响因子：
10.5
通讯作者：
Cong F
中科院分区：
文献类型：
--
作者：
Ji L;Jiang B;Jiang X;Charlat O;Chen A;Mickanin C;Bauer A;Xu W;Yan X;Cong F
在这项研究中，Ji等人鉴定SIAH 1/2（SIAH）为介导Wnt诱导的Axin降解的E3连接酶。他们的结果表明，Wnt诱导的Axin/GSK 3复合物的解离允许SIAH与Axin相互作用并促进其降解，这代表了实现持续Wnt/β-catenin信号传导的重要前馈机制。Wnt/β-catenin信号通路在胚胎发育和成体组织稳态中起重要作用。Axin是一种浓度限制因子，负责β-连环蛋白破坏复合物的形成。Wnt信号本身促进Axin的降解。然而，Axin的这种靶向作用的潜在分子机制和生物学相关性尚未阐明。在这里，我们确定SIAH 1/2（SIAH）作为E3连接酶介导Wnt诱导的Axin降解。SIAH蛋白通过与Axin的GSK 3结合结构域中的一个CNOP基序相互作用促进Axin的泛素化和蛋白酶体降解，并且SIAH的这种功能被GSK 3与Axin的结合所抵消。结构分析显示，负责SIAH结合的Axin片段也参与GSK 3结合，但在Axin/SIAH和Axin/GSK 3复合物中采用不同的构象。敲除SIAH 1可阻断Wnt诱导的Axin泛素化并减弱Wnt诱导的β-连环蛋白稳定化。我们的数据表明，Wnt诱导的Axin/GSK 3复合物的解离允许SIAH与不与GSK 3相关的Axin相互作用并促进其降解，并且SIAH介导的Axin降解代表了实现持续Wnt/β-连环蛋白信号传导的重要前馈机制。
In this study, Ji et al. identify SIAH1/2 (SIAH) as the E3 ligase mediating Wnt-induced Axin degradation. Their results suggest that Wnt-induced dissociation of the Axin/GSK3 complex allows SIAH to interact with Axin and promote its degradation, which represents an important feed-forward mechanism to achieve sustained Wnt/β-catenin signaling. The Wnt/β-catenin signaling pathway plays essential roles in embryonic development and adult tissue homeostasis. Axin is a concentration-limiting factor responsible for the formation of the β-catenin destruction complex. Wnt signaling itself promotes the degradation of Axin. However, the underlying molecular mechanism and biological relevance of this targeting of Axin have not been elucidated. Here, we identify SIAH1/2 (SIAH) as the E3 ligase mediating Wnt-induced Axin degradation. SIAH proteins promote the ubiquitination and proteasomal degradation of Axin through interacting with a VxP motif in the GSK3-binding domain of Axin, and this function of SIAH is counteracted by GSK3 binding to Axin. Structural analysis reveals that the Axin segment responsible for SIAH binding is also involved in GSK3 binding but adopts distinct conformations in Axin/SIAH and Axin/GSK3 complexes. Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination and attenuates Wnt-induced β-catenin stabilization. Our data suggest that Wnt-induced dissociation of the Axin/GSK3 complex allows SIAH to interact with Axin not associated with GSK3 and promote its degradation and that SIAH-mediated Axin degradation represents an important feed-forward mechanism to achieve sustained Wnt/β-catenin signaling.