Hedgehog（Hh）信号通路在动物发育过程中起着关键的作用，Hh信号通路调控失调导致发育缺陷相关疾病，并可能导致癌症。Ptc蛋白作为Hh信号途径的受体分子负调控Hh途径。已有果蝇的研究表明，结合了Hh配体的Ptc蛋白 (ligand-bound Ptc)与未结合配体的Ptc蛋白(ligand-unbound Ptc)之间的比例对于调控Hh信号的活性非常重要，但生物体内如何控制 ligand-bound和ligand-unbound Ptc之间的比例的机制还不清楚。

　　中科院动物研究所陈大华研究组利用果蝇和斑马鱼为模式，通过与多个研究组合作发现Smurf泛素连接酶跟Ptc蛋白有物理相互作用；Smurf作为泛素连接酶调控Ptc蛋白的泛素化修饰和蛋白降解。果蝇和斑马鱼的实验结果表明：Smurf通过位点特异性的泛素化来修饰Ptc蛋白，正调控了Hh信号通路的活性，进一步的研究发现，在Hh信号通路被激活的情况下，该信号通路的下游信号转导蛋白Smo能促进Smurf选择性地泛素化修饰ligand-unbound Ptc并介导其降解。

    数学建模分析表明，Smo对于Smurf在降解ligand-unbound Ptc方面的起促进作用, 这一机制有利于生物体内信号受体细胞对外源Hh信号进行有效的解读，并在维持信号的稳定传递上起重要作用。

　　动物所陈大华、陶毅、刘峰和孙钦秒等研究组以及上海生化细胞所赵允研究组合作完成这一工作，研究成果于11月26日发表于PLOS Biology。该研究工作得到了科技部、国家自然科学基金和科学院干细胞先导专项的支持。

原文摘要：

Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover

Hedgehog signaling plays conserved roles in controlling embryonic development; its dysregulation has been implicated in many human diseases including cancers. Hedgehog signaling has an unusual reception system consisting of two transmembrane proteins, Patched receptor and Smoothened signal transducer. Although activation of Smoothened and its downstream signal transduction have been intensively studied, less is known about how Patched receptor is regulated, and particularly how this regulation contributes to appropriate Hedgehog signal transduction. Here we identified a novel role of Smurf E3 ligase in regulating Hedgehog signaling by controlling Patched ubiquitination and turnover. Moreover, we showed that Smurf-mediated Patched ubiquitination depends on Smo activity in wing discs. Mechanistically, we found that Smo interacts with Smurf and promotes it to mediate Patched ubiquitination by targeting the K1261 site in Ptc. The further mathematic modeling analysis reveals that a bidirectional control of activation of Smo involving Smurf and Patched is important for signal-receiving cells to precisely interpret external signals, thereby maintaining Hedgehog signaling reliability. Finally, our data revealed an evolutionarily conserved role of Smurf proteins in controlling Hh signaling by targeting Ptc during development.

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