Adenosine deaminase acting on RNA-1 (ADAR1) inhibits hepatitis B virus (HBV) replication by enhancing microRNA-122 processing
Adenosine deaminase acting on RNA-1 (ADAR1) inhibits hepatitis B virus (HBV) replication by enhancing microRNA-122 processing
复制标题
作用于 RNA-1 (ADAR1) 的腺苷脱氨酶通过增强 microRNA-122 加工来抑制乙型肝炎病毒 (HBV) 复制
DOI：
10.1074/jbc.ra119.007970
复制
发表时间：
2019-09-20
影响因子：
4.8
通讯作者：
Li, Linghua
中科院分区：
文献类型：
--
作者：
Liu, Guangyan;Ma, Xiancai;Li, Linghua
作用于 RNA-1 (ADAR1) 的腺苷脱氨酶涉及腺苷至肌苷 RNA 编辑和 microRNA 加工。 ADAR1 已知参与多种病毒的复制，包括丙型肝炎和丁型肝炎。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 在人肝细胞中具有两种剪接亚型：组成型 p110 蛋白和干扰素-α (IFN-α) 反应性 p150 蛋白。我们发现 ADAR1 的过度表达会降低 HBV 培养模型中的 HBV RNA。催化位点突变体 ADAR1 也会降低 HBV RNA 水平，而另一种作用于 RNA (ADAR) 家族蛋白的腺苷脱氨酶 ADAR2 则不会。此外，通过 IFN-α 刺激诱导 ADAR1 也降低了 HBV RNA 水平。通过敲除或敲除来降低内源性 ADAR1 表达，从而增加 HBV RNA 水平。一种主要的肝细胞特异性 microRNA，miRNA-122，被发现与 ADAR1 表达呈正相关，外源性 miRNA-122 降低了 HBV RNA 和 DNA，而相反，转染 miRNA-122 抑制剂则增加了它们。 ADAR1 表达导致的 HBV RNA 减少被 p53 敲低所消除，表明 p53 参与了 ADAR1 介导的 HBV RNA 减少。这项研究首次证明 ADAR1 通过增加肝细胞中 miRNA-122 的水平来发挥抗 HBV 感染的抗病毒作用。
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.