IFN-α刺激ADAR1通过RNA编辑来下调MAVS的表达以调节抗HBV反应

StephenW

ADAR1 stimulation by IFN-α downregulates the expression of MAVS via RNA editing to regulate the anti-HBV response
Tao Li  1 , Xiaoshuang Yang  1 , Wei Li  2 , Jiaru Song  1 , Zhuo Li  3 , Xilin Zhu  1 , Xiaopan Wu  4 , Ying Liu  5
Affiliations
Affiliations

    1
    State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College. Beijing, 100005, P. R. China.
    2
    Department of Interventional Radiology, the Affiliated Hospital of Qingdao University, Shandong 266003, China.
    3
    Department of Infectious Disease, Affiliated You'an Hospital, Capital University of Medical Science, Beijing 100069, China.
    4
    State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College. Beijing, 100005, P. R. China. Electronic address: [email protected].
    5
    State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College. Beijing, 100005, P. R. China. Electronic address: [email protected].

    PMID: 33279720 DOI: 10.1016/j.ymthe.2020.11.031

Abstract

The partial response of CHB patients to IFN-α therapy remains elusive, which requires a better understanding of the involved molecular mechanism. In our study, bioinformatics analysis was applied to relate IFN-α regulated candidate genes and RNA editing sites by RNA sequencing. 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-α therapy were confirmed in CHB patients. We found that IFN-α downregulates MAVS via RNA editing that was mediated by ADAR1. ADAR1 inhibited MAVS expression via a HuR-mediated post-transcriptional regulation. MAVS exerted an antiviral activity and reduced the level of HBV markers in vitro and in vivo. IFN-α antiviral effects were significantly enhanced by MAVS co-transfection. HBc interacted with SP1 to inhibit the promoter activity of MAVS that regulate its expression. CHB patients with a rs3746662A allele had higher MAVS expression, thus were more responsive to IFN-α treatment. In this work we demonstrated that the decrease of MAVS expression is mediated by the IFN-α -ADAR1 axis. This study also highlighted the potential for the clinical application of MAVS in combination with IFN-α for the treatment of HBV infection.

Keywords: RNA editing; adenosine deaminase acting on RNA; hepatitis B virus; mitochondrial antiviral signaling protein; polymorphism.

Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved

StephenW

IFN-α刺激ADAR1通过RNA编辑来下调MAVS的表达以调节抗HBV反应
桃李1，杨小双1，魏丽2，宋佳如1，卓丽3，朱锡麟1，吴晓盼4，刘颖5
隶属关系
隶属关系

    1个
    中国医学科学院基础医学研究所医学分子生物学国家重点实验室北京协和医学院基础医学院。北京，100005。
    2
    青岛大学附属医院介入放射科，山东266003。
    3
    首都医科大学附属佑安医院传染病科，北京100069
    4
    中国医学科学院基础医学研究所医学分子生物学国家重点实验室北京协和医学院基础医学院。北京，100005。电子地址：[email protected]。
    5
    中国医学科学院基础医学研究所医学分子生物学国家重点实验室北京协和医学院基础医学院。北京，100005。电子地址：[email protected]。

    PMID：33279720 DOI：10.1016 / j.ymthe.2020.11.031

抽象

CHB患者对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，生物信息学分析通过RNA测序技术应用于关联IFN-α调控的候选基因和RNA编辑位点。在HepG2.2.15细胞和两个小鼠模型中均证实了MAVS抗病毒作用。 CHB患者中证实了MAVS基因多态性与对IFN-α治疗的反应之间的关联。我们发现，IFN-α通过ADAR1介导的RNA编辑下调MAVS。 ADAR1通过HuR介导的转录后调控抑制MAVS表达。 MAVS在体外和体内均具有抗病毒活性并降低了HBV标记物的水平。 MAVS共转染可显着增强IFN-α的抗病毒作用。 HBc与SP1相互作用以抑制调节其表达的MAVS的启动子活性。具有rs3746662A等位基因的CHB患者具有较高的MAVS表达，因此对IFN-α治疗反应更强。在这项工作中，我们证明了MAVS表达的降低是由IFN-α-ADAR1轴介导的。这项研究还强调了MAVS与IFN-α结合用于治疗HBV感染的临床应用潜力。

关键字：RNA编辑；腺苷脱氨酶作用于RNA；乙型肝炎病毒;线粒体抗病毒信号蛋白；多态性。

版权所有©2020美国基因与细胞治疗学会。由Elsevier Inc.出版。保留所有权利。