ADAR1 Stimulation by IFN-α Downregulates the Expression of MAVS via RNA Editing to Regulate the Anti-HBV Response
ADAR1 Stimulation by IFN-α Downregulates the Expression of MAVS via RNA Editing to Regulate the Anti-HBV Response
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DOI：
10.1016/j.ymthe.2020.11.031
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发表时间：
2021-03-03
影响因子：
12.4
通讯作者：
Liu, Ying
中科院分区：
文献类型：
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作者：
Li, Tao;Yang, Xiaoshuang;Liu, Ying
慢性乙型肝炎病毒（CHB）患者对干扰素- α (ifn - α)治疗的部分反应仍然难以捉摸，这需要更好地了解所涉及的分子机制。在我们的研究中，通过RNA测序，应用生物信息学分析将ifn - α调控的候选基因与RNA编辑位点联系起来。在HepG2.2.15细胞和两种小鼠模型中证实了线粒体抗病毒信号蛋白（MAVS）的抗病毒作用。在CHB患者中证实了MAVS基因多态性与ifn - α治疗反应之间的关联。我们发现ifn - α通过作用于RNA的腺苷脱氨酶（ADAR1）介导的RNA编辑下调MAVS。ADAR1通过人抗原R (HuR)介导的转录后调控抑制MAVS的表达。MAVS在体内和体外均具有抗病毒活性，并能降低乙型肝炎病毒（HBV）标志物的水平。MAVS共转染显著增强ifn - α抗病毒作用。乙型肝炎核心蛋白（HBc）与SP1相互作用，抑制MAVS启动子活性，调控其表达。携带rs3746662A等位基因的CHB患者具有更高的MAVS表达，因此对ifn - α治疗更敏感。在这项工作中，我们证明了ifn - α - adar1轴介导了MAVS表达的降低。该研究还强调了MAVS联合ifn - α治疗HBV感染的临床应用潜力。
The partial response of chronic hepatitis B virus (CHB) patients to interferon-alpha (IFN-alpha) therapy remains elusive, which requires a better understanding of the involved molecular mechanism. In our study, bioinformatics analysis was applied to relate IFN-alpha regulated candidate genes and RNA editing sites by RNA sequencing. Mitochondrial antiviral signaling protein (MAVS) antiviral effect was confirmed in HepG2.2.15 cells and in two mouse models. The associations between polymorphisms in MAVS gene and response to IFN-alpha therapy were confirmed in CHB patients. We found that IFN-alpha downregulates MAVS via RNA editing that was mediated by adenosine deaminase acting on RNA (ADAR1). ADAR1 inhibited MAVS expression via a human antigen R (HuR)-mediated post-transcriptional regulation. MAVS exerted an antiviral activity and reduced the level of hepatitis B virus (HBV) markers in vitro and in vivo. IFN-alpha antiviral effects were significantly enhanced by MAVS co-transfection. Hepatitis B core protein (HBc) interacted with SP1 to inhibit the promoter activity of MAVS that regulates its expression. CHB patients with a rs3746662A allele had higher MAVS expression and thus were more responsive to IFN-alpha treatment. In this work, we demonstrated that the decrease of MAVS expression is mediated by the IFN-alpha-ADAR1 axis. This study also highlighted the potential for the clinical application of MAVS in combination with IFN-alpha for the treatment of HBV infection.