H2O2 induces PP2A demethylation to downregulate mTORC1 signaling in HEK293 cells
H2O2 induces PP2A demethylation to downregulate mTORC1 signaling in HEK293 cells
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H2O2 诱导 PP2A 去甲基化，下调 HEK293 细胞中的 mTORC1 信号传导
DOI：
10.1002/cbin.10987
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发表时间：
2018
影响因子：
3.9
通讯作者：
Li Xiyi
中科院分区：
文献类型：
--
作者：
Tang Shen;Qin Fu;Wang Xinhang;Liang Ziwei;Cai Haiqing;Mo Laiming;Huang Yue;Liang Boyin;Wei Xuejing;Ao Qingqing;Xu Yilu;Liu Yuyang;Xiao Deqiang;Guo Songchao;Lu Cailing;Li Xiyi
哺乳动物雷帕霉素靶蛋白（mTOR）是一种Ser/Thr蛋白激酶，作为ATP和氨基酸传感器，通过介导促分裂原和营养依赖性信号转导来控制细胞生长和增殖。蛋白磷酸酶2A（PP 2A）是一种广泛表达的丝氨酸/苏氨酸磷酸酶，负调节mTOR信号传导。PP 2A的甲基化由亮氨酸羧基甲基转移酶-1（LCMT 1）催化，并由蛋白磷酸酶甲基酯酶1（PME-1）逆转，后者调节PP 2A的活性和底物特异性。然而，PP 2A甲基化是否与mTOR信号转导有关仍然是未知的。在这项研究中，我们研究了PP 2A甲基化对氧化应激下HEK 293细胞中mTOR信号传导的影响。我们的研究结果表明，氧化应激诱导PP 2A去甲基化和抑制mTORC 1信号通路。接下来，我们研究了在氧化应激下阻断PP 2A去甲基化的两种策略。一种策略是使用PME-1抑制剂防止PP 2A去甲基化;另一种策略是通过LCMT 1的过表达激活PP 2A甲基化。结果表明，PME-1抑制剂和LCMT 1过表达均阻止了氧化应激诱导的mTORC 1信号转导抑制。此外，LCMT 1过表达挽救了细胞活力和线粒体膜电位降低，以响应氧化应激。这些结果表明H2 O2诱导PP 2A去甲基化，下调mTORC 1信号转导。这些发现为氧化应激下PP 2A去甲基化和mTORC 1信号转导的调节提供了一种新的机制。
Mammalian target of rapamycin (mTOR) is a Ser/Thr protein kinase that functions as an ATP and amino acid sensor to govern cell growth and proliferation by mediating mitogen‐ and nutrient‐dependent signal transduction. Protein phosphatase 2A (PP2A), a ubiquitously expressed serine/threonine phosphatase, negatively regulates mTOR signaling. Methylation of PP2A is catalyzed by leucine carboxyl methyltransferase‐1 (LCMT1) and reversed by protein phosphatase methylesterase 1 (PME‐1), which regulates PP2A activity and substrate specificity. However, whether PP2A methylation is related to mTOR signaling is still unknown. In this study, we examined the effect of PP2A methylation on mTOR signaling in HEK293 cells under oxidative stress. Our results show that oxidative stress induces PP2A demethylation and inhibits the mTORC1 signaling pathway. Next, we examined two strategies to block PP2A demethylation under oxidative stress. One strategy was to prevent PP2A demethylation using a PME‐1 inhibitor; the other strategy was to activate PP2A methylation via overexpression of LCMT1. The results show that both the PME‐1 inhibitor and LCMT1 overexpression prevent the mTORC1 signaling suppression induced by oxidative stress. Additionally, LCMT1 overexpression rescued cell viability and the mitochondrial membrane potential decrease in response to oxidative stress. These results demonstrate that H2O2induces PP2A demethylation to downregulate mTORC1 signaling. These findings provide a novel mechanism for the regulation of PP2A demethylation and mTORC1 signaling under oxidative stress.