In the absence of Hedgehog ligand, patched-1 (Ptch1) localizes to cilia and prevents ciliary accumulation and activation of smoothened (Smo). Upon ligand binding, Ptch1 is removed from cilia, and Smo is derepressed and accumulates in cilia where it activates signaling. The mechanisms regulating these dynamic movements are not well understood, but defects in intraflagellar transport components, including Ift27 and the BBSome, cause Smo to accumulate in cilia without pathway activation. We find that in the absence of ligand-induced pathway activation, Smo is ubiquitinated and removed from cilia, and this process is dependent on Ift27 and BBSome components. Activation of Hedgehog signaling decreases Smo ubiquitination and ciliary removal, resulting in its accumulation. Blocking ubiquitination of Smo by an E1 ligase inhibitor or by mutating two lysine residues in intracellular loop three causes Smo to aberrantly accumulate in cilia without pathway activation. These data provide a mechanism to control Smo’s ciliary level during Hedgehog signaling by regulating the ubiquitination state of the receptor.

中文翻译：

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泛素与鞭毛内运输的连接变得平滑，以调节 Hedgehog 信号传导

在没有 Hedgehog 配体的情况下，patched-1 (Ptch1) 定位于纤毛并防止纤毛积累和 smoothened (Smo) 激活。配体结合后，Ptch1 从纤毛中去除，Smo 被解除抑制并在纤毛中积聚，激活信号传导。调节这些动态运动的机制尚不清楚，但鞭毛内运输组件（包括 Ift27 和 BBSome）的缺陷导致 Smo 在纤毛中积累，而没有途径激活。我们发现，在没有配体诱导的通路激活的情况下，Smo 被泛素化并从纤毛中去除，并且该过程依赖于 Ift27 和 BBSome 组件。Hedgehog 信号的激活会减少 Smo 泛素化和纤毛去除，从而导致其积累。通过 E1 连接酶抑制剂或通过突变细胞内三环中的两个赖氨酸残基来阻断 Smo 的泛素化，会导致 Smo 在纤毛中异常积累，而没有途径激活。这些数据提供了一种机制，通过调节受体的泛素化状态，在 Hedgehog 信号传导过程中控制 Smo 的纤毛水平。