Laboratory of Nutritional Biochemistry, Department of Agricultural Chemistry, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo, 156-8502, Japan.
Sci Rep. 2020 Dec 3;10(1):21160. doi: 10.1038/s41598-020-78274-6.
Mutations in genes that encode components of tuberous sclerosis complex 2 (TSC2) are associated with tuberous sclerosis complex disease. TSC2 interacts with tuberous sclerosis complex 1 to form a complex that negatively regulates cell growth and proliferation via the inactivation of mechanistic target of rapamycin complex 1. The activity of TSC2 is mainly regulated via posttranslational modifications such as phosphorylation. However, the control of TSC2 activity is not entirely achieved by phosphorylation. In this study, we show that TSC2 is methylated at R1457 and R1459 by protein arginine methyltransferase 1 (PRMT1). Methylation of these two residues can affect the phosphorylation status through protein kinase B (Akt) of TSC2 at T1462 and is essential for TSC2 stability. Taken together, these findings indicate that novel posttranslational modifications are important for the regulation of TSC2 stability through PRMT1-mediated methylation.
基因突变编码结节性硬化症复合物 2 (TSC2) 的成分与结节性硬化症有关。TSC2 与结节性硬化症复合物 1 相互作用形成一个复合物，通过抑制雷帕霉素靶蛋白复合物 1 的失活来负调控细胞生长和增殖。TSC2 的活性主要通过翻译后修饰（如磷酸化）来调节。然而，TSC2 活性的控制并非完全通过磷酸化来实现。在这项研究中，我们表明 TSC2 被蛋白精氨酸甲基转移酶 1（PRMT1）在 R1457 和 R1459 处甲基化。这两个残基的甲基化可以通过 TSC2 的蛋白激酶 B（Akt）在 T1462 处影响磷酸化状态，并且对 TSC2 的稳定性是必需的。总之，这些发现表明，通过 PRMT1 介导的甲基化，新的翻译后修饰对 TSC2 稳定性的调节很重要。
