Demethylase JMJD6 as a New Regulator of Interferon Signaling: Effects of HCV and Ethanol Metabolism.
Demethylase JMJD6 as a New Regulator of Interferon Signaling: Effects of HCV and Ethanol Metabolism.
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DOI：
10.1016/j.jcmgh.2017.10.004
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发表时间：
2018
影响因子：
7.2
通讯作者：
Osna NA
中科院分区：
文献类型：
--
作者：
Ganesan M;Tikhanovich I;Vangimalla SS;Dagur RS;Wang W;Poluektova LI;Sun Y;Mercer DF;Tuma D;Weinman SA;Kharbanda KK;Osna NA
酒精诱导的丙型肝炎病毒（HCV）感染进展与肝细胞先天免疫功能障碍有关。内源性干扰素(IFN)α通过触发Janus激酶信号转导和转录激活因子1 （STAT1）通路诱导干扰素刺激基因（ISGs）的激活。这种激活需要蛋白甲基转移酶1调节STAT1的精氨酸甲基化。在这里，我们旨在研究STAT1甲基化是否也依赖于去甲基化酶jumonji结构域6蛋白（JMJD6）的水平，以及乙醇和HCV是否影响肝细胞中JMJD6的表达。将Huh7.5-CYP （RLW）细胞和肝细胞分别暴露于乙醛生成系统（AGS）和50 mmol/L乙醇中。实时聚合酶链反应和Western blot检测JMJD6信使RNA和蛋白的表达。对ifn α激活的JMJD6过表达或JMJD6低表达的细胞进行STAT1甲基化、ISG激活和HCV RNA检测。体内研究已在C57Bl/6小鼠（表达或不表达HCV结构蛋白）或具有人源化肝脏的嵌合小鼠中进行，这些小鼠分别饲喂对照或乙醇饲料。暴露于AGS的细胞上调了RLW细胞中JMJD6的表达。乙醇处理原代肝细胞证实了这一结果。前甲基化剂甜菜碱逆转了AGS/乙醇的作用。在小鼠体内，分别饲喂添加和不添加甜菜碱的对照/乙醇，得到了类似的结果。JMJD6过表达抑制STAT1甲基化、ifn α-诱导的ISG激活，并增加HCV-RNA水平。相比之下，JMJD6沉默增强了STAT1甲基化，IFNα刺激ISG，减弱了Huh7.5细胞中HCV-RNA的表达。我们得出结论，JMJD6抑制STAT1的精氨酸甲基化。HCV和乙醛都会增加JMJD6水平，从而损害暴露于病毒和/或酒精的肝细胞的STAT1甲基化和先天免疫保护。
Alcohol-induced progression of hepatitis C virus (HCV) infection is related to dysfunction of innate immunity in hepatocytes. Endogenously produced interferon (IFN)α induces activation of interferon-stimulated genes (ISGs) via triggering of the Janus kinase–signal transducer and activator of transcription 1 (STAT1) pathway. This activation requires protein methyltransferase 1–regulated arginine methylation of STAT1. Here, we aimed to study whether STAT1 methylation also depended on the levels of demethylase jumonji domain-containing 6 protein (JMJD6) and whether ethanol and HCV affect JMJD6 expression in hepatocytes. Huh7.5-CYP (RLW) cells and hepatocytes were exposed to acetaldehyde-generating system (AGS) and 50 mmol/L ethanol, respectively. JMJD6 messenger RNA and protein expression were measured by real-time polymerase chain reaction and Western blot. IFNα-activated cells either overexpressing JMJD6 or with knocked-down JMJD6 expression were tested for STAT1 methylation, ISG activation, and HCV RNA. In vivo studies have been performed on C57Bl/6 mice (expressing HCV structural proteins or not) or chimeric mice with humanized livers fed control or ethanol diets. AGS exposure to cells up-regulated JMJD6 expression in RLW cells. These results were corroborated by ethanol treatment of primary hepatocytes. The promethylating agent betaine reversed the effects of AGS/ethanol. Similar results were obtained in vivo, when mice were fed control/ethanol with and without betaine supplementation. Overexpression of JMJD6 suppressed STAT1 methylation, IFNα-induced ISG activation, and increased HCV-RNA levels. In contrast, JMJD6 silencing enhanced STAT1 methylation, ISG stimulation by IFNα, and attenuated HCV-RNA expression in Huh7.5 cells. We conclude that arginine methylation of STAT1 is suppressed by JMJD6. Both HCV and acetaldehyde increase JMJD6 levels, thereby impairing STAT1 methylation and innate immunity protection in hepatocytes exposed to the virus and/or alcohol.
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影响因子：
4.6
作者：
Chen CF;Feng X;Liao HY;Jin WJ;Zhang J;Wang Y;Gong LL;Liu JJ;Yuan XH;Zhao BB;Zhang D;Chen GF;Wan Y;Guo J;Yan HP;He YW
通讯作者：
He YW
影响因子：
29.4
作者：
Duong, FHT;Filipowicz, M;Heim, MH
通讯作者：
Heim, MH
DOI：
10.1111/acer.13226
发表时间：
2016-11
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Ganesan M;Poluektova LY;Tuma DJ;Kharbanda KK;Osna NA
通讯作者：
Osna NA
影响因子：
6.4
作者：
McCartney, Erin M.;Semendric, Ljiljana;Beard, Michael R.
通讯作者：
Beard, Michael R.
影响因子：
82.9
作者：
Mercer, DF;Schiller, DE;Kneteman, NM
通讯作者：
Kneteman, NM