Dengue Virus Subverts Host Innate Immunity by Targeting Adaptor Protein MAVS
Dengue Virus Subverts Host Innate Immunity by Targeting Adaptor Protein MAVS
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登革热病毒通过靶向接头蛋白 MAVS 破坏宿主先天免疫
DOI：
10.1128/jvi.00221-16
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发表时间：
2016-08-01
影响因子：
5.4
通讯作者：
Li, Mengfeng
中科院分区：
文献类型：
--
作者：
He, Zhenjian;Zhu, Xun;Li, Mengfeng
摘要登革病毒（DENV）是最常见的蚊媒病毒感染人类，目前是一个严重的全球性健康挑战。为了在其宿主细胞中建立感染，DENV必须破坏干扰素（IFN）的产生和/或抗病毒作用。本研究的目的是了解登革病毒抑制IFN产生的机制。我们确定DENV NS 4A与线粒体抗病毒信号蛋白（MAVS）相互作用，MAVS先前被发现激活NF-κB和IFN调节因子3（IRF 3），从而在与线粒体相关的内质网膜（MAMs）中诱导I型IFN。我们进一步证明NS 4A与MAVS的N-末端CARD样（CL）结构域和C-末端跨膜（TM）结构域相关。这种关联阻止了MAVS与RIG-I的结合，导致RIG-I诱导的IRF 3活化的抑制，从而导致IFN产生的消除。总的来说，我们的研究结果说明了DENV逃避宿主免疫系统的新分子机制，并为抗DENV策略提供了新的靶点。I型干扰素（IFN）是机体抵御病毒入侵的第一道防线。为了成功地建立感染，登革病毒（DENV）必须抵消IFN的产生或功能。登革病毒抑制IFN产生的机制知之甚少。在这项研究中，我们证明了DENV NS 4A蛋白通过结合MAVS和破坏RIG-I-MAVS相互作用在抑制干扰素产生中起重要作用。我们的研究表明，MAVS是NS 4A的一个新的宿主靶标，并为DENV逃避宿主先天免疫应答提供了分子机制。这些发现对于理解DENV的发病机制具有重要意义，并可能为使用NS 4A作为治疗和/或预防靶点提供新的见解。
ABSTRACT Dengue virus (DENV) is the most common mosquito-borne virus infecting humans and is currently a serious global health challenge. To establish infection in its host cells, DENV must subvert the production and/or antiviral effects of interferon (IFN). The aim of this study was to understand the mechanisms by which DENV suppresses IFN production. We determined that DENV NS4A interacts with mitochondrial antiviral signaling protein (MAVS), which was previously found to activate NF-κB and IFN regulatory factor 3 (IRF3), thus inducing type I IFN in the mitochondrion-associated endoplasmic reticulum membranes (MAMs). We further demonstrated that NS4A is associated with the N-terminal CARD-like (CL) domain and the C-terminal transmembrane (TM) domain of MAVS. This association prevented the binding of MAVS to RIG-I, resulting in the repression of RIG-I-induced IRF3 activation and, consequently, the abrogation of IFN production. Collectively, our findings illustrate a new molecular mechanism by which DENV evades the host immune system and suggest new targets for anti-DENV strategies. IMPORTANCE Type I interferon (IFN) constitutes the first line of host defense against invading viruses. To successfully establish infection, dengue virus (DENV) must counteract either the production or the function of IFN. The mechanism by which DENV suppresses IFN production is poorly understood and characterized. In this study, we demonstrate that the DENV NS4A protein plays an important role in suppressing interferon production through binding MAVS and disrupting the RIG-I–MAVS interaction in mitochondrion-associated endoplasmic reticulum membranes (MAMs). Our study reveals that MAVS is a novel host target of NS4A and provides a molecular mechanism for DENV evasion of the host innate immune response. These findings have important implications for understanding the pathogenesis of DENV and may provide new insights into using NS4A as a therapeutic and/or prevention target.