title: Glucocorticoid-induced S-adenosylmethionine enhances the interferon signaling pathway by restoring STAT1 protein methylation in hepatitis B virus-infected cells.
abstract: Patients with chronic hepatitis B usually exhibit a low response to treatment with interferon α (IFN-α). An alternative approach to increase the response rate of IFN-α might be to immunologically stimulate the host with glucocorticoids (GCs) before treatment with IFN-α, but the underlying mechanism remains unclear. We hypothesized that the GCs enhance IFN signaling by inducing S-adenosylmethionine (AdoMet) when hepatitis B virus (HBV) replication was effectively suppressed by IFN-α. Here, we investigated the effect of GCs and IFN-α on AdoMet production and methionine adenosyltransferase 1A (MAT1A) expression in vitro. Furthermore, we determined whether post-transcriptional regulation is involved in HBV-repressed MAT1A expression and AdoMet production induced by dexamethasone (Dex). We found that AdoMet homeostasis was disrupted by Dex and that Dex directly regulated MAT1A expression by enhancing the binding of the glucocorticoid receptor (GR) to the glucocorticoid-response element (GRE) of the MAT1A promoter. HBV reduced AdoMet production by increasing methylation at GRE sites within the MAT1A promoter. The X protein of hepatitis B virus led to hypermethylation in the MAT1A promoter by recruiting DNA methyltransferase 1, and it inhibited GR binding to the GRE in the MAT1A promoter. Dex could increase an antiviral effect by inducing AdoMet production via a positive feedback loop when HBV is effectively suppressed by IFN-α, and the mechanism that involves Dex-induced AdoMet could increase STAT1 methylation rather than STAT1 phosphorylation. These findings provide a possible mechanism by which GC-induced AdoMet enhances the antiviral activity of IFN-α by restoring STAT1 methylation in HBV-infected cells.
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Bing
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Siying
authors.initials: S
authors.lastname: Zhu
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Guozheng
authors.initials: G
authors.lastname: Yu
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Liu
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Li
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Yitao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Haolong
authors.initials: H
authors.lastname: Qi
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Yueming
authors.initials: Y
authors.lastname: He
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China spss2005@126.com.
authors.forename: Zhisu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: From the Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China lqy@whu.edu.cn.
authors.forename: Quanyan
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D016898:Interferon-alpha / Q000494:pharmacology*; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012436:S-Adenosylmethionine / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D005938:Glucocorticoids; D016898:Interferon-alpha; D011965:Receptors, Glucocorticoid; D050794:STAT1 Transcription Factor; D012436:S-Adenosylmethionine; D003907:Dexamethasone; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C506577:MAT1A protein, human; D008716:Methionine Adenosyltransferase
keywords: Glucocorticoid; Hepatitis Virus; Interferon; Liver Cancer; S-Adenosylmethionine (AdoMet)