MCPIP1通过使病毒RNA不稳定来抑制乙型肝炎病毒复制，并负面

StephenW

Antiviral Res. 2020 Jan 8:104705. doi: 10.1016/j.antiviral.2020.104705. [Epub ahead of print]
MCPIP1 inhibits Hepatitis B virus replication by destabilizing viral RNA and negatively regulates the virus-induced innate inflammatory responses.
Li M1, Yang J2, Zhao Y3, Song Y2, Yin S4, Guo J5, Zhang H2, Wang K2, Wei L2, Li S6, Xu W7.
Author information

1
    Institute of Biology and Medical Sciences, Soochow University, Building, 703, 199 Ren-ai Road, Suzhou, 215123, China. Electronic address: [email protected].
2
    Institute of Biology and Medical Sciences, Soochow University, Building, 703, 199 Ren-ai Road, Suzhou, 215123, China.
3
    Central Laboratory, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, 200031, China.
4
    Department of Infectious Diseases, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 21008, China.
5
    Department of Microbiology and Immunology, Stanford University, Stanford, CA, 94305, United States.
6
    Central Laboratory, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, 200031, China. Electronic address: [email protected].
7
    Institute of Biology and Medical Sciences, Soochow University, Building, 703, 199 Ren-ai Road, Suzhou, 215123, China. Electronic address: [email protected].

Abstract

Monocyte chemotactic protein-induced protein 1 (MCPIP1) is an inflammatory regulator in immune response. Recently, MCPIP1 has also been identified as a host antiviral factor against certain virus infection including human immunodeficiency virus, dengue virus and hepatitis C virus. However, whether MCPIP1 could restrict the replication of hepatitis B virus (HBV), a DNA pararetrovirus belonging to Hepadnaviridae family, has not been investigated. In this study, we found that MCPIP1 expression was up-regulated in mouse livers upon acute HBV replication and in HBV-replicated hepatoma cells or HBV-stimulated macrophages. Enforced MCPIP1 expression by hydrodynamic DNA injection in vivo significantly inhibited HBV replication in the mouse livers. Then in vitro studies by overexpression or knockdown assays in cell-lines identified the direct antiviral effect of MCPIP1 on HBV replication. RNA immunoprecipitation and decay assay further suggested that MCPIP1 potently restricted HBV replication through directly binding viral RNA and degrading RNA via its RNase activity, but not deubiquitinase activity. Moreover, we further verified that MCPIP1 negatively regulated HBV-induced proinflammatory cytokines, such as IL-1β, TNF-α and IL-6 in macrophages. Taken together, our data expand MCPIP1's range of viral targets to DNA virus and also demonstrate the negative regulatory role of MCPIP1 in suppressing virus-induced inflammatory response, suggesting MCPIP1 as a potential therapeutic target for treating HBV-related diseases via inducing a host defense against HBV and reducing inflammatory injury meanwhile.

Copyright © 2020. Published by Elsevier B.V.
KEYWORDS:

HBV; Inflammatory cytokines; MCPIP1; RNase

PMID:
    31926181
DOI:
    10.1016/j.antiviral.2020.104705

StephenW

抗病毒水库。 2020年1月8日：104705。 doi：10.1016 / j.antiviral.2020.104705。 [Epub提前发布]
MCPIP1通过使病毒RNA不稳定来抑制乙型肝炎病毒复制，并负面调节病毒引起的先天性炎症反应。
李M1，杨J2，赵Y3，宋Y2，尹S4，郭J5，张H2，王K2，魏L2，李S6，徐W7。
作者信息

1个
    苏州大学生物医学研究所，江苏苏州仁爱路199号703楼，邮编215123。电子地址：[email protected]。
2
    苏州大学生物医学研究所，江苏苏州仁爱路199号703楼，邮编215123。
3
    复旦大学附属上海中山大学附属徐汇中心医院中心实验室，上海200031
4
    南京大学医学院附属南京鼓楼医院传染病科，江苏南京21008。
5
    斯坦福大学微生物学和免疫学系，美国加利福尼亚州斯坦福，94305。
6
    复旦大学附属上海中山大学附属徐汇中心医院中心实验室，上海200031电子地址：[email protected]。
7
    苏州大学生物医学研究所，江苏苏州仁爱路199号703楼，邮编215123。电子地址：[email protected]。

抽象

单核细胞趋化蛋白诱导蛋白1（MCPIP1）是免疫反应中的炎症调节剂。最近，MCPIP1还被确定为针对某些病毒感染的宿主抗病毒因子，其中包括人类免疫缺陷病毒，登革热病毒和丙型肝炎病毒。但是，尚未研究MCPIP1是否可以限制乙型肝炎病毒（HBV）的复制，乙型肝炎病毒属于Hepadnaviridae家族的DNA副逆转录病毒。在这项研究中，我们发现小鼠肝中急性HBV复制和HBV复制的肝癌细胞或HBV刺激的巨噬细胞中MCPIP1的表达上调。通过体内流体动力学DNA注射增强的MCPIP1表达可显着抑制小鼠肝脏中的HBV复制。然后，通过在细胞系中进行过表达或敲低试验的体外研究，确定了MCPIP1对HBV复制的直接抗病毒作用。 RNA免疫沉淀和衰减试验进一步表明，MCPIP1通过直接结合病毒RNA和通过其RNase活性而不是去泛素酶活性降解RNA来有效限制HBV复制。此外，我们进一步证实，MCPIP1在巨噬细胞中负调控HBV诱导的促炎细胞因子，如IL-1β，TNF-α和IL-6。综上所述，我们的数据将MCPIP1的病毒靶标范围扩大到了DNA病毒，并且还证明了MCPIP1在抑制病毒诱导的炎症反应中的负调节作用，表明MCPIP1作为通过诱导宿主防御以治疗HBV相关疾病的潜在治疗靶标同时降低乙肝病毒和炎性损伤。

版权所有©2020。由Elsevier B.V.发布。
关键字：

乙肝病毒炎性细胞因子； MCPIP1；核糖核酸酶

PMID：
    31926181
DOI：
    10.1016 / j.antiviral.2020.104705