PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2
PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2
复制标题
DOI：
10.1016/j.cmet.2023.11.001
复制
发表时间：
2023-12-05
期刊：
影响因子：
29
通讯作者：
Wei，Wenyi
中科院分区：
文献类型：
--
作者：
Jiang，Cong;Liu，Jing;Wei，Wenyi
蛋氨酸是决定mTORC 1激活的多种营养输入的一个重要分支。在不存在甲硫氨酸的情况下，SAMTOR与GATOR 1结合并抑制mTORC 1信号传导。然而，mTORC 1如何在甲硫氨酸刺激后被激活仍然很难理解。在这里，我们报告说，PRMT 1感甲硫氨酸/SAM利用SAM作为辅因子的酶活性为基础的调节mTORC 1信号。在甲硫氨酸充足的条件下，升高的胞质SAM从GATOR 1释放SAMTOR，这赋予PRMT 1与GATOR 1的缔合。随后，SAM负载的PRMT 1甲基化GATOR 1的催化亚基NPRL 2，从而抑制其GAP活性并导致mTORC 1活化。值得注意的是，PRMT 1的遗传或药理学抑制阻碍了mTORC 1对肝脏甲硫氨酸的感知，并改善了老年小鼠的胰岛素敏感性，确立了PRMT 1介导的甲硫氨酸感知在生理水平上的作用。因此，PRMT 1与SAMTOR协调以形成mTORC 1信号传导的甲硫氨酸传感装置。
Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive. Here, we report that PRMT1 senses methionine/SAM by utilizing SAM as a cofactor for an enzymatic activity-based regulation of mTORC1 signaling. Under methionine-sufficient conditions, elevated cytosolic SAM releases SAMTOR from GATOR1, which confers the association of PRMT1 with GATOR1. Subsequently, SAM-loaded PRMT1 methylates NPRL2, the catalytic subunit of GATOR1, thereby suppressing its GAP activity and leading to mTORC1 activation. Notably, genetic or pharmacological inhibition of PRMT1 impedes hepatic methionine sensing by mTORC1 and improves insulin sensitivity in aged mice, establishing the role of PRMT1-mediated methionine sensing at physiological levels. Thus, PRMT1 coordinates with SAMTOR to form the methionine-sensing apparatus of mTORC1 signaling.