Intracellular signaling by the pleiotropic cytokine transforming growth factor-β (TGF-β) is inhibited by Smad7 in a feedback control mechanism. The activity of Smad7 is tightly regulated by multiple post-translational modifications. Using resin-assisted capture and metabolic labeling methods, we show here that Smad7 is S-palmitoylated in mammary epithelial cell models that are widely studied because of their strong responses to TGF-β and their biological relevance to mammary development and tumor progression. S-palmitoylation of Smad7 is mediated by zDHHC17, a member of a family of 23 S-acyltransferase enzymes. Moreover, we identified four cysteine residues (Cys202, Cys225, Cys415, and Cys417) in Smad7 as palmitoylation acceptor sites. S-palmitoylation of Smad7 on Cys415 and Cys417 promoted the translocation of Smad7 from the nucleus to the cytoplasm, enhanced the stability of the Smad7 protein, and enforced its inhibitory effect on TGF-β-induced Smad transcriptional response. Thus, our findings reveal a new post-translational modification of Smad7, and highlight an important role of S-palmitoylation to enhance inhibition of TGF-β/Smad signaling by Smad7.

中文翻译：

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S-酰基转移酶 zDHHC17 对 Smad7 棕榈酰化增强其对 TGF-β/Smad 信号传导的抑制作用


Smad7 在反馈控制机制中抑制多效细胞因子转化生长因子-β (TGF-β) 的细胞内信号传导。 Smad7 的活性受到多种翻译后修饰的严格调控。使用树脂辅助捕获和代谢标记方法，我们在此表明​​ Smad7 在乳腺上皮细胞模型中被 S-棕榈酰化，这些模型因其对 TGF-β 的强烈反应及其与乳腺发育和肿瘤进展的生物学相关性而被广泛研究。 Smad7 的 S-棕榈酰化由 zDHHC17 介导，zDHHC17 是 23 个 S-酰基转移酶家族的成员。此外，我们确定了 Smad7 中的四个半胱氨酸残基（Cys202、Cys225、Cys415 和 Cys417）作为棕榈酰化受体位点。 Smad7 在 Cys415 和 Cys417 上的 S-棕榈酰化促进了 Smad7 从细胞核易位到细胞质，增强了 Smad7 蛋白的稳定性，并增强了其对 TGF-β 诱导的 Smad 转录反应的抑制作用。因此，我们的研究结果揭示了 Smad7 的一种新的翻译后修饰，并强调了 S-棕榈酰化在增强 Smad7 对 TGF-β/Smad 信号传导抑制方面的重要作用。