Porcine Deltacoronavirus Nucleocapsid Protein Suppressed IFN-β Production by Interfering Porcine RIG-I dsRNA-Binding and K63-Linked Polyubiquitination
Porcine Deltacoronavirus Nucleocapsid Protein Suppressed IFN-β Production by Interfering Porcine RIG-I dsRNA-Binding and K63-Linked Polyubiquitination
复制标题
猪 Delta 冠状病毒核衣壳蛋白通过干扰猪 RIG-I dsRNA 结合和 K63 连接的多泛素化抑制 IFN-β 产生
DOI：
10.3389/fimmu.2019.01024
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发表时间：
2019-05-09
影响因子：
7.3
通讯作者：
Yan Yaxian
中科院分区：
文献类型：
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作者：
Ji Likai;Li Shasha;Yan Yaxian
猪三角洲冠状病毒（Porcine deltacoronavirus，PDCoV）是一种新发现的引起仔猪特别是新生仔猪严重呕吐和腹泻的猪冠状病毒。自2014年以来，PDCoV在全球范围内爆发，给养猪业造成重大经济损失。干扰素（IFN）介导的抗病毒反应是病毒与宿主相互作用的重要组成部分，在抑制病毒感染中起着重要作用。然而，PDCoV逃避猪免疫监视的机制尚不清楚。在本研究中，我们证明了PDCoV核衣壳（N）蛋白拮抗水泡性口炎病毒（VSV）感染或poly（I：C）刺激后猪IFN-b的产生。PDCoV N蛋白在猪RLR信号分子刺激下也抑制猪IFN-β启动子的激活。PDCoV N蛋白通过与猪视黄酸诱导基因I（pRIG-I）和猪肿瘤坏死因子受体相关因子3（pTRAF 3）直接相互作用靶向它们。PDCoV N蛋白的N端（1-246 aa）是与pRIG-Ⅰ相互作用并干扰其功能的重要区域。我们证实PDCoV N通过与pRIG-I结合以阻止其结合双链RNA来拮抗IFN-β的产生。此外，猪Riplet（pRiplet）通过介导K63连接的多聚泛素化而成为pRIG-I的重要激活剂。然而，PDCoV N蛋白抑制pRiplet结合pRIG-I以抑制pRIG-I K63连接的多聚泛素化。总之，我们的研究结果揭示了一种新的机制，PDCoV N蛋白干扰宿主抗病毒反应中pRIG-I的早期激活。新的发现为PDCoV逃避宿主先天免疫反应提供了新的见解，并可能为PDCoV感染提供新的治疗靶点和更有效的疫苗策略。
Porcine deltacoronavirus (PDCoV) is a newly detected porcine coronavirus causing serious vomiting and diarrhea in piglets, especially newborn piglets. There has been an outbreak of PDCoV in worldwide since 2014, causing significant economic losses in the pig industry. The interferon (IFN)-mediated antiviral response is an important component of virus-host interactions and plays an essential role in inhibiting virus infection. However, the mechanism of PDCoV escaping the porcine immune surveillance is unclear. In the present study, we demonstrated that the PDCoV nucleocapsid (N) protein antagonizes porcine IFN-b production after vesicular stomatitis virus (VSV) infection or poly(I: C) stimulation. PDCoV N protein also suppressed the activation of porcine IFN-beta promoter when it was stimulated by porcine RLR signaling molecules. PDCoV N protein targeted porcine retinoic acid-inducible gene I (pRIG-I) and porcine TNF receptor associated factor 3 (pTRAF3) by directly interacting with them. The N-terminal region (1-246 aa) of PDCoV N protein was important for interacting with pRIG-I and interfere its function. We confirmed that PDCoV N antagonizes IFN-beta production by associating with pRIG-I to impede it from binding double-stranded RNA. Furthermore, porcine Riplet (pRiplet) was an important activator for pRIG-I by mediating the K63-linked polyubiquitination. However, PDCoV N protein restrained the pRiplet binding pRIG-I to inhibit pRIG-I K63-linked polyubiquitination. Taken together, our results revealed a novel mechanism by which PDCoV N protein interferes with the early activation of pRIG-I in the host antiviral response. The novel findings provide a new insight into PDCoV on evading the host innate immune response and may provide new therapeutic targets and more efficacious vaccines strategies for PDCoV infections.