From fly to mammals, the Smaug/Samd4 family of prion‐like RNA ‐binding proteins control gene expression by destabilizing and/or repressing the translation of numerous target transcripts. However, the regulation of its activity remains poorly understood. We show that Smaug's protein levels and mRNA repressive activity are downregulated by Hedgehog signaling in tissue culture cells. These effects rely on the interaction of Smaug with the G‐protein coupled receptor Smoothened, which promotes the phosphorylation of Smaug by recruiting the kinase Fused. The activation of Fused and its binding to Smaug are sufficient to suppress its ability to form cytosolic bodies and to antagonize its negative effects on endogenous targets. Importantly, we demonstrate in vivo that HH reduces the levels of smaug mRNA and increases the level of several mRNA s downregulated by Smaug. Finally, we show that Smaug acts as a positive regulator of Hedgehog signaling during wing morphogenesis. These data constitute the first evidence for a post‐translational regulation of Smaug and reveal that the fate of several mRNA s bound to Smaug is modulated by a major signaling pathway.

中文翻译：

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GPCR对RNA结合蛋白Smaug的调节通过融合的激酶使之平滑。

从果蝇到哺乳动物，S病毒样RNA结合蛋白的Smaug / Samd4家族通过破坏和/或抑制众多靶转录物的翻译来控制基因表达。然而，对其活性的调节仍知之甚少。我们显示，Smaug的蛋白质水平和mRNA抑制活性被组织培养细胞中的刺猬信号下调。这些作用依赖于Smaug与G蛋白偶联受体Smoothened的相互作用，后者通过募集融合的激酶来促进Smaug的磷酸化。Fused的激活及其与Smaug的结合足以抑制其形成胞质体的能力，并拮抗其对内源性靶标的负面影响。重要的是，我们在体内证明了HH可降低smaug的水平mRNA并增加Smaug下调的几个mRNA的水平。最后，我们显示Smaug在机翼形态发生过程中充当Hedgehog信号的正向调节剂。这些数据构成了Smaug的翻译后调控的第一个证据，并揭示了与Smaug结合的几种mRNA的命运受到主要信号通路的调节。