Demethylase JMJD6 as a New Regulator of Interferon Signaling: Effects of HCV and Ethanol Metabolism
| Autor: | Murali Ganesan, Shiva Shankar Vangimalla, Larisa Poluektova, Raghubendra Singh Dagur, Weimin Wang, David F. Mercer, Irina Tikhanovich, Kusum K. Kharbanda, Natalia A. Osna, Yimin Sun, Steven A. Weinman, Dean J. Tuma |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Methyltransferase AMI-1 protein arginine N-methyltransferase inhibitor OA okadaic acid 0302 clinical medicine STAT1 PCR polymerase chain reaction Interferon AGS acetaldehyde-generating system PP2A protein phosphatase 2A OAS-1 2’-5’-oligoadenylate synthetase-1 siRNA short interfering RNA Original Research BHMT betaine-homocysteine-S-methyltransferase Gastroenterology CYP2E1 cytochrome P450 2E1 SAM S-adenosylmethionine Methylation mRNA messenger RNA OASL 2’-5’-oligoadenylate synthetase-like protein Biochemistry HCV hepatitis C virus HCV 030211 gastroenterology & hepatology Alcohol medicine.drug JAK-STAT Janus kinase–STAT signal transducer and activator of transcription Biology ADH alcohol dehydrogenase JMJD6 jumonji domain-containing 6 protein 03 medical and health sciences cDNA complementary DNA RT reverse-transcription JMJD6 medicine ISG interferon-stimulated gene IFN interferon lcsh:RC799-869 Ethanol metabolism Messenger RNA Innate immune system Hepatology Molecular biology Ach acetaldehyde 030104 developmental biology TK-NOG thymidine kinase transgene-NOD/Shi-scid/IL-2Rγnull mice biology.protein Demethylase lcsh:Diseases of the digestive system. Gastroenterology PRMT1 protein methyl transferase 1 4-MP 4-methylpirazole |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 5, Iss 2, Pp 101-112 (2018) |
| ISSN: | 2352-345X |
| Popis: | Background & Aims 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. Methods 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. Results 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. Conclusions 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. Graphical abstract |
| Databáze: | OpenAIRE |
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