College of Basic Medical Sciences, Shenyang Medical College, Shenyang 110034, China.
Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China.
J Biol Chem. 2019 Sep 20;294(38):14043-14054. doi: 10.1074/jbc.RA119.007970. Epub 2019 Jul 30.
Adenosine deaminases acting on RNA-1 (ADAR1) involves adenosine to inosine RNA editing and microRNA processing. ADAR1 is known to be involved in the replication of various viruses, including hepatitis C and D. However, the role of ADAR1 in hepatitis B virus (HBV) infection has not yet been elucidated. Here, for the first time, we demonstrated ADAR1 antiviral activity against HBV. ADAR1 has two splicing isoforms in human hepatocytes: constitutive p110 protein and interferon-α (IFN-α)-responsive p150 protein. We found that overexpression of ADAR1 decreased HBV RNA in an HBV culture model. A catalytic-site mutant ADAR1 also decreased HBV RNA levels, whereas another adenosine deaminases that act on the RNA (ADAR) family protein, ADAR2, did not. Moreover, the induction of ADAR1 by stimulation with IFN-α also reduced HBV RNA levels. Decreases in endogenous ADAR1 expression by knock-down or knock-out increased HBV RNA levels. A major hepatocyte-specific microRNA, miRNA-122, was found to be positively correlated with ADAR1 expression, and exogenous miRNA-122 decreased both HBV RNA and DNA, whereas, conversely, transfection with a miRNA-122 inhibitor increased them. The reduction of HBV RNA by ADAR1 expression was abrogated by p53 knock-down, suggesting the involvement of p53 in the ADAR1-mediated reduction of HBV RNA. This study demonstrated, for the first time, that ADAR1 plays an antiviral role against HBV infection by increasing the level of miRNA-122 in hepatocytes.
RNA 结合酶腺苷脱氨酶 1（ADAR1）参与腺嘌呤向肌苷的 RNA 编辑和 microRNA 加工。ADAR1 已知参与多种病毒的复制，包括丙型和丁型肝炎病毒。然而，ADAR1 在乙型肝炎病毒（HBV）感染中的作用尚未阐明。在这里，我们首次证明了 ADAR1 对 HBV 的抗病毒活性。ADAR1 在人肝细胞中有两种剪接异构体：组成型 p110 蛋白和干扰素-α（IFN-α）反应性 p150 蛋白。我们发现，ADAR1 的过表达降低了 HBV 培养模型中的 HBV RNA。催化位点突变的 ADAR1 也降低了 HBV RNA 水平，而另一种 RNA 腺苷脱氨酶（ADAR）家族蛋白 ADAR2 则没有。此外，IFN-α 刺激诱导 ADAR1 的表达也降低了 HBV RNA 水平。通过敲低或敲除降低内源性 ADAR1 表达会增加 HBV RNA 水平。发现主要的肝细胞特异性 microRNA，miRNA-122，与 ADAR1 表达呈正相关，外源性 miRNA-122 降低了 HBV RNA 和 DNA 的水平，而相反，转染 miRNA-122 抑制剂则增加了它们的水平。ADAR1 表达降低 HBV RNA 的作用被 p53 敲低所阻断，表明 p53 参与了 ADAR1 介导的 HBV RNA 降低。这项研究首次证明，ADAR1 通过增加肝细胞中 miRNA-122 的水平发挥抗病毒作用，抵抗 HBV 感染。
