Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, Uppsala, Sweden.
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, Uppsala, Sweden.
J Biol Chem. 2024 Jul;300(7):107462. doi: 10.1016/j.jbc.2024.107462. Epub 2024 Jun 12.
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.
多功能细胞因子转化生长因子-β（TGF-β）通过 Smad7 进行细胞内信号转导，这一过程受 Smad7 反馈控制机制的抑制。Smad7 的活性受到多种翻译后修饰的严格调控。在此，我们通过树脂辅助捕获和代谢标记方法显示，Smad7 在乳腺上皮细胞模型中发生 S-棕榈酰化，这些模型因对 TGF-β 的强烈反应以及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 是一个包含 23 种 S-酰基转移酶的家族成员。此外，我们鉴定了 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 上 Cys415 和 Cys417 的 S-棕榈酰化促进了 Smad7 从核内到细胞质的易位，增强了 Smad7 蛋白的稳定性，并加强了其对 TGF-β 诱导的 Smad 转录反应的抑制作用。因此，我们的发现揭示了 Smad7 的一种新的翻译后修饰，并强调了 S-棕榈酰化在增强 Smad7 抑制 TGF-β/Smad 信号转导中的重要作用。
