PRMT1 suppresses ATF4-mediated endoplasmic reticulum response in cardiomyocytes
PRMT1 suppresses ATF4-mediated endoplasmic reticulum response in cardiomyocytes
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DOI：
10.1038/s41419-019-2147-3
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发表时间：
2019-12-02
影响因子：
9
通讯作者：
Kang, Jong-Sun
中科院分区：
文献类型：
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作者：
Jeong, Myong-Ho;Jeong, Hyeon-Ju;Kang, Jong-Sun
内质网（ER）应激信号在控制细胞生存或死亡方面发挥着关键作用。持续的ER应激激活涉及ATF 4/CHOP轴的促凋亡途径。虽然越来越多的证据支持其在心血管疾病中的重要作用，但其机制尚不清楚。在这里，我们证明了PRMT 1在心肌细胞ER应激控制中的关键作用。抑制PRMT 1可增强衣霉素（TN）诱导的心肌细胞内质网应激反应，而过表达PRMT 1则可减弱TN诱导的内质网应激反应。有趣的是，ATF 4耗竭减弱了PRMT 1抑制诱导的ER应激反应。具有精氨酸239转换为赖氨酸的ATF 4的甲基化缺陷突变体加剧了ER应激，伴随着响应于TN的促凋亡切割的Caspase 3和磷酸化-. H2 AX的水平提高。机制研究表明，PRMT 1通过甲基化调节ATF 4的蛋白质稳定性。总之，我们的数据表明，ATF 4甲基化精氨酸239的PRMT 1是一种新的调节机制，保护心肌细胞从ER应激诱导的细胞死亡。
Endoplasmic reticulum (ER) stress signaling plays a critical role in the control of cell survival or death. Persistent ER stress activates proapoptotic pathway involving the ATF4/CHOP axis. Although accumulating evidences support its important contribution to cardiovascular diseases, but its mechanism is not well characterized. Here, we demonstrate a critical role for PRMT1 in the control of ER stress in cardiomyocytes. The inhibition of PRMT1 augments tunicamycin (TN)-triggered ER stress response in cardiomyocytes while PRMT1 overexpression attenuates it. Consistently, PRMT1 null hearts show exacerbated ER stress and cell death in response to TN treatment. Interestingly, ATF4 depletion attenuates the ER stress response induced by PRMT1 inhibition. The methylation-deficient mutant of ATF4 with the switch of arginine 239 to lysine exacerbates ER stress accompanied by enhanced levels of proapoptotic cleaved Caspase3 and phosphorylated-.H2AX in response to TN. The mechanistic study shows that PRMT1 modulates the protein stability of ATF4 through methylation. Taken together, our data suggest that ATF4 methylation on arginine 239 by PRMT1 is a novel regulatory mechanism for protection of cardiomyocytes from ER stress-induced cell death.