Glucocorticoid-induced S-Adenosylmethionine Enhances the Interferon Signaling Pathway by Restoring STAT1 Protein Methylation in Hepatitis B Virus-infected Cells
Glucocorticoid-induced S-Adenosylmethionine Enhances the Interferon Signaling Pathway by Restoring STAT1 Protein Methylation in Hepatitis B Virus-infected Cells
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糖皮质激素诱导的 S-腺苷甲硫氨酸通过恢复乙型肝炎病毒感染细胞中 STAT1 蛋白甲基化来增强干扰素信号通路
DOI：
10.1074/jbc.m114.589689
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发表时间：
2014-11-21
影响因子：
4.8
通讯作者：
Liu, Quanyan
中科院分区：
文献类型：
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作者：
Bing, Yuntao;Zhu, Siying;Liu, Quanyan
慢性B型肝炎患者通常对干扰素α（IFN-α）治疗反应较低。另一种增加IFN-α应答率的方法可能是在IFN-α治疗前用糖皮质激素（GC）免疫刺激宿主，但其潜在机制尚不清楚。我们假设，当IFN-α有效抑制B型肝炎病毒（HBV）复制时，GC通过诱导S-腺苷甲硫氨酸（S-adenosylmethionine，S-Met）增强IFN信号传导。在这里，我们研究了GC和IFN-α对体外蛋氨酸生产和蛋氨酸腺苷转移酶1A（MAT 1A）表达的影响。此外，我们确定转录后调节是否参与HBV抑制的MAT 1A表达和地塞米松（Dex）诱导的MET产生。我们发现Dex破坏了MAT 1A的体内平衡，Dex通过增强糖皮质激素受体（GR）与MAT 1A启动子的糖皮质激素反应元件（GRE）的结合直接调节MAT 1A的表达。HBV通过增加MAT 1A启动子内GRE位点的甲基化来减少BMPMet的产生。乙型肝炎B病毒的X蛋白通过募集DNA甲基转移酶1导致MAT 1A启动子超甲基化，并抑制GR与MAT 1A启动子中的GRE结合。当HBV被IFN-α有效抑制时，Dex可以通过正反馈回路诱导STAT 1产生来增加抗病毒作用，并且涉及Dex诱导的STAT 1甲基化而不是STAT 1磷酸化的机制可能增加STAT 1甲基化。这些发现提供了一种可能的机制，通过这种机制，GC诱导的IFN-α通过恢复HBV感染细胞中的STAT 1甲基化来增强IFN-α的抗病毒活性。
Patients with chronic hepatitis B usually exhibit a low response to treatment with interferon alpha (IFN-alpha). An alternative approach to increase the response rate of IFN-alpha might be to immunologically stimulate the host with glucocorticoids (GCs) before treatment with IFN-alpha, 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-alpha. Here, we investigated the effect of GCs and IFN-alpha 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-alpha, 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-alpha by restoring STAT1 methylation in HBV-infected cells.