Hippo Stabilises Its Adaptor Salvador by Antagonising the HECT Ubiquitin Ligase Herc4.
Hippo Stabilises Its Adaptor Salvador by Antagonising the HECT Ubiquitin Ligase Herc4.
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DOI：
10.1371/journal.pone.0131113
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Tapon N
中科院分区：
文献类型：
--
作者：
Aerne BL;Gailite I;Sims D;Tapon N
通过Hippo（Hpo）途径的信号传导涉及激酶级联，其导致促生长转录辅激活因子Yorkie（Yki）的磷酸化和失活。尽管鉴定了大量的通路成员和调节剂，但我们对导致Hpo和下游激酶Warts（Wts）活化的分子事件的理解仍然不完整。最近，几个Hpo途径组分的靶向降解已被证明是调节途径活性的一种手段。特别是，支架蛋白萨尔瓦多（Sav），这被认为是促进Hpo/Wts协会的稳定性，是至关重要的依赖于其结合伴侣Hpo。在基于细胞的RNAi筛选涉及Sav稳定性的泛素调节剂中，我们将HECT结构域蛋白Herc 4（含有HECT和RLD结构域的E3连接酶）鉴定为Sav E3连接酶。Herc 4表达促进Sav泛素化和降解，而Herc 4耗竭稳定Sav。有趣的是，Hpo以激酶依赖性方式降低Sav/Herc 4相互作用。这表明存在一个正反馈循环，其中Hpo通过拮抗Herc 4介导的Sav降解来稳定其自身的正调节因子。
Signalling through the Hippo (Hpo) pathway involves a kinase cascade, which leads to the phosphorylation and inactivation of the pro-growth transcriptional co-activator Yorkie (Yki). Despite the identification of a large number of pathway members and modulators, our understanding of the molecular events that lead to activation of Hpo and the downstream kinase Warts (Wts) remain incomplete. Recently, targeted degradation of several Hpo pathway components has been demonstrated as a means of regulating pathway activity. In particular, the stability of scaffold protein Salvador (Sav), which is believed to promote Hpo/Wts association, is crucially dependent on its binding partner Hpo. In a cell-based RNAi screen for ubiquitin regulators involved in Sav stability, we identify the HECT domain protein Herc4 (HECT and RLD domain containing E3 ligase) as a Sav E3 ligase. Herc4 expression promotes Sav ubiquitylation and degradation, while Herc4 depletion stabilises Sav. Interestingly, Hpo reduces Sav/Herc4 interaction in a kinase-dependent manner. This suggests the existence of a positive feedback loop, where Hpo stabilises its own positive regulator by antagonising Herc4-mediated degradation of Sav.
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