Research Center on Aging, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Beijing, People's Republic of China.
Research Center on Aging, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Beijing, People's Republic of China
Mol Cell Biol. 2018 Nov 13;38(23). doi: 10.1128/MCB.00414-18. Print 2018 Dec 1.
The cellular senescence-inhibited gene (CSIG) is implicated in important biological processes, including cellular senescence and apoptosis. Our work showed that CSIG is involved in the myristoylation of the serine/threonine protein phosphatase PPM1A. Previous research has shown that myristoylation is necessary for PPM1A to dephosphorylate Smad2 and Smad3. However, the control and the biological significance of the myristoylation remain poorly understood. In this study, we found that CSIG knockdown disturbs PPM1A myristoylation and reduces the dephosphorylation by PPM1A of its substrate Smad2. By regulating PPM1A myristoylation, CSIG is involved in modulating the signaling of transforming growth factor β (TGF-β). Further study of the mechanism indicated that CSIG facilitates the interaction between -myristoyltransferase 1 (NMT1) and PPM1A. Taking the data together, we found that CSIG is a regulator of PPM1A myristoylation and TGF-β signaling. By promoting the myristoylation of PPM1A, CSIG enhanced the phosphatase activity of PPM1A and further inhibited TGF-β signaling. This work not only extends the biological significance of CSIG but also provides new ideas and a reference for the study of the regulatory mechanism of myristoylation.
细胞衰老抑制基因（CSIG）参与多种重要的生物学过程，包括细胞衰老和凋亡。我们的工作表明 CSIG 参与丝氨酸/苏氨酸蛋白磷酸酶 PPM1A 的豆蔻酰化。先前的研究表明，豆蔻酰化对于 PPM1A 去磷酸化 Smad2 和 Smad3 是必需的。然而，豆蔻酰化的调控及其生物学意义仍知之甚少。在这项研究中，我们发现 CSIG 敲低干扰了 PPM1A 的豆蔻酰化，降低了 PPM1A 对其底物 Smad2 的去磷酸化作用。通过调节 PPM1A 的豆蔻酰化，CSIG 参与调节转化生长因子β（TGF-β）信号转导。对机制的进一步研究表明，CSIG 促进了 -豆蔻酰转移酶 1（NMT1）和 PPM1A 之间的相互作用。综合这些数据，我们发现 CSIG 是 PPM1A 豆蔻酰化和 TGF-β信号转导的调节剂。通过促进 PPM1A 的豆蔻酰化，CSIG 增强了 PPM1A 的磷酸酶活性，进一步抑制了 TGF-β信号转导。这项工作不仅扩展了 CSIG 的生物学意义，也为豆蔻酰化调控机制的研究提供了新的思路和参考。
