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PRMT1 suppresses ATF4-mediated endoplasmic reticulum response in cardiomyocytes.

ABSTRACT: 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.

SUBMITTER: Jeong MH

PROVIDER: S-EPMC6885520 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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PRMT1 suppresses ATF4-mediated endoplasmic reticulum response in cardiomyocytes.

Jeong Myong-Ho MH Jeong Hyeon-Ju HJ Ahn Byeong-Yun BY Pyun Jung-Hoon JH Kwon Ilmin I Cho Hana H Kang Jong-Sun JS

Cell death & disease 20191202 12

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 respon ...[more]

PMID: 31787756

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Project description:ObjectiveActivating transcription factor 4 (ATF4) is a transcriptional regulator of the unfolded protein response and integrated stress response (ISR) that promote the restoration of normal endoplasmic reticulum (ER) function. Previous reports demonstrated that dysregulation of the ISR led to development of severe diabetes. However, the contribution of ATF4 to pancreatic β-cells remains poorly understood. In this study, we aimed to analyze the effect of ISR enhancer Sephin1 and ATF4-deficient β-cells to clarify the role of ATF4 in β-cells under ER stress conditions.MethodsTo examine the role of ATF4 in vivo, ISR enhancer Sephin1 (5 mg/kg body weight, p.o.) was administered daily for 21 days to Akita mice. We also established β-cell-specific Atf4 knockout (βAtf4-KO) mice that were further crossed with Akita mice. These mice were analyzed for characteristics of diabetes, β-cell function, and morphology of the islets. To identify the downstream factors of ATF4 in β-cells, the islets of βAtf4-KO mice were subjected to cDNA microarray analyses. To examine the transcriptional regulation by ATF4, we also performed in situ PCR analysis of pancreatic sections from mice and ChIP-qPCR analysis of CT215 β-cells.ResultsAdministration of the ISR enhancer Sephin1 improved glucose metabolism in Akita mice. Sephin1 also increased the insulin-immunopositive area and ATF4 expression in the pancreatic islets. Akita/βAtf4-KO mice exhibited dramatically exacerbated diabetes, shown by hyperglycemia at an early age, as well as a remarkably short lifespan owing to diabetic ketoacidosis. Moreover, the islets of Akita/βAtf4-KO mice presented increased numbers of cells stained for glucagon, somatostatin, and pancreatic polypeptide and increased expression of aldehyde dehydrogenase 1 family member 3, a marker of dedifferentiation. Using microarray analysis, we identified atonal BHLH transcription factor 8 (ATOH8) as a downstream factor of ATF4. Deletion of ATF4 in β-cells showed reduced Atoh8 expression and increased expression of undifferentiated markers, Nanog and Pou5f1. Atoh8 expression was also abolished in the islets of Akita/βAtf4-KO mice.ConclusionsWe conclude that transcriptional regulation by ATF4 maintains β-cell identity via ISR modulation. This mechanism provides a promising target for the treatment of diabetes.

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PRMT1 suppresses ATF4-mediated endoplasmic reticulum response in cardiomyocytes.

Publications

PRMT1 suppresses ATF4-mediated endoplasmic reticulum response in cardiomyocytes.

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