The Cellular Senescence-Inhibited Gene Is Essential for PPM1A Myristoylation To Modulate Transforming Growth Factor β Signaling

Abstract

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.

N-Myristoyltransferase as a Glycine and Lysine Myristoyltransferase in Cancer, Immunity, and Infections

“…There is also evidence for substrate-specific regulation of NMT activity. The cellular senescence-inhibited gene (CSIG) was shown to enhance the interaction between NMT1 and the serine/threonine protein phosphatase PPM1A promoting PPM1A myristoylation, which enhances its phosphatase activity on SMAD2 to inhibit TFG-β signaling . Other interactions might regulate NMT localization.…”

“…The cellular senescence-inhibited gene (CSIG) was shown to enhance the interaction between NMT1 and the serine/threonine protein phosphatase PPM1A promoting PPM1A myristoylation, which enhances its phosphatase activity on SMAD2 to inhibit TFG-β signaling. 25 Other interactions might regulate NMT localization. While NMT is thought to be largely cytosolic, its interactions with calnexin 26 and ribosomes 27 are thought to keep some of the enzyme at the endoplasmic reticulum.…”

PPM1A as a key target of the application of Jiawei‑Maxing‑Shigan decoction for the attenuation of radiation‑induced epithelial‑mesenchymal transition in type II alveolar epithelial cells

“…PPM1A is a phosphatase of the serine/threonine PPM family and the main substrates of PPM1A include MAPK, Smad2 and Smad3 and MKKs ( 12 – 14 ). PPM1A serves an important role in the signal transduction of TGF-β/Smad signaling and can inactivate TGF-β/Smad signaling by dephosphorylating Smad2/3 ( 26 , 27 ) ( Fig. 7 ).…”

A Not-So-Ancient Grease History: Click Chemistry and Protein Lipid Modifications

“…The CSIG protein facilitates N-myristoylation of PPM1A by mediating the NMT−PPM1A interaction. 332 Evidence for a CSIG-PPM1A-NMT complex was obtained by coimmunoprecipitation, and reduced Alk-C14 labeling of PPM1A was observed upon CSIG knockdown. Indeed, the use of clickable analogues of myristic acid not only directly validates the myristoyl modification on proteins but also can indirectly confirm the role of this lipid modification in the assembly of protein complexes.…”

“…Furthermore, N -myristoylation can be controlled by proteins that modulate the interaction between NMTs and their substrates. The CSIG protein facilitates N -myristoylation of PPM1A by mediating the NMT–PPM1A interaction . Evidence for a CSIG-PPM1A-NMT complex was obtained by coimmunoprecipitation, and reduced Alk-C14 labeling of PPM1A was observed upon CSIG knockdown.…”