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Volume 38 Issue 3
June 2023

    . doi: 10.1016/j.virs.2023.03.003
    Citation: Xiangju Wu, Lei Chen, Chao Sui, Yue Hu, Dandan Jiang, Fan Yang, Laura C. Miller, Juntong Li, Xiaoyan Cong, Nataliia Hrabchenko, Changhee Lee, Yijun Du, Jing Qi. 3Cpro of FMDV inhibits type II interferon-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation .VIROLOGICA SINICA, 2023, 38(3) : 387-397.  http://dx.doi.org/10.1016/j.virs.2023.03.003
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    口蹄疫病毒3C蛋白通过阻断STAT1核易位抑制II型干扰素诱导的JAK-STAT信号通路

    • a. 山东省农业科学院畜牧兽医研究所, 山东省畜禽疫病防治与繁育重点实验室/农业农村部畜禽生物组学重点实验室;山东省农业科学院农作物种质资源研究所, 中国 济南 250100;

    • b. 山东师范大学生命科学学院, 中国 济南 250358;

    • c. 中国农业科学院兰州兽医研究所, 兽医病原生物学国家重点实验室/国家口蹄疫参考实验室/农业部动物病毒学重点实验室, 中国 兰州 730050;

    • d. 堪萨斯州立大学兽医学院诊断医学和病理生物学系, 美国 曼哈顿 66506;

    • e. 庆尚国立大学兽医学院和病毒疫苗研究中心, 韩国 晋州 52828

    • 口蹄疫病毒（FMDV）通过多种策略对抗宿主先天免疫。FMDV L蛋白和3C蛋白通过不同的机制干扰I型干扰素。FMDV结构蛋白VP3降解Janus激酶1抑制γ干扰素信号转导。是否有FMDV非结构蛋白抑制II型干扰素信号通路尚不清楚。本研究结果显示，感染建立后，FMDV对γ干扰素处理具有抵抗力，FMDV抑制了II型干扰素诱导的干扰素刺激基因（ISG）的表达。我们首次发现，口蹄疫病毒非结构蛋白3C通过阻断STAT1核易位拮抗γ干扰素诱导的JAK-STAT信号通路。3C蛋白显著降低了ISGs的转录水平和GAS启动子活性，而不影响STAT1的蛋白质水平、酪氨酸磷酸化和同源二聚化。同时，3C蛋白酶活性在降解KPNA1中发挥重要作用，通过增强KPNA1表达水平，抑制ISGs mRNA和GAS启动子活性。我们的结果揭示了FMDV非结构蛋白拮抗宿主II型IFN信号通路的新机制。

    3Cpro of FMDV inhibits type II interferon-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation

    • a. Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of Agricultural Sciences, Jinan, 250100, China;

    • b. College of Life Science, Shandong Normal University, Jinan, 250358, China;

    • c. State Key Laboratory of Veterinary Etiological Biology/National Foot and Mouth Disease Reference Laboratory/Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China;

    • d. Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, 66506, USA;

    • e. College of Veterinary Medicine and Virus Vaccine Research Center, Gyeongsang National University, Jinju, 52828, Republic of Korea

    • Foot-and-mouth disease virus (FMDV) has developed various strategies to antagonize the host innate immunity. FMDV Lpro and 3Cpro interfere with type I IFNs through different mechanisms. The structural protein VP3 of FMDV degrades Janus kinase 1 to suppress IFN-γ signaling transduction. Whether non-structural proteins of FMDV are involved in restraining type II IFN signaling pathways is unknown. In this study, it was shown that FMDV replication was resistant to IFN-γ treatment after the infection was established and FMDV inhibited type II IFN induced expression of IFN-γ-stimulated genes (ISGs). We also showed for the first time that FMDV non-structural protein 3C antagonized IFN-γ-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation. 3Cpro expression significantly reduced the ISGs transcript levels and palindromic gamma-activated sequences (GAS) promoter activity, without affecting the protein level, tyrosine phosphorylation, and homodimerization of STAT1. Finally, we provided evidence that 3C protease activity played an essential role in degrading KPNA1 and thus inhibited ISGs mRNA and GAS promoter activities. Our results reveal a novel mechanism by which an FMDV non-structural protein antagonizes host type II IFN signaling.
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      3Cpro of FMDV inhibits type II interferon-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation

        Corresponding author: Yijun Du, duyijun0916@163.com
        Corresponding author: Jing Qi, qj-happy2008@163.com
      • a. Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and Veterinary Medicine, Institute of Crop Germplasm Resources, Shandong Academy of Agricultural Sciences, Jinan, 250100, China;
      • b. College of Life Science, Shandong Normal University, Jinan, 250358, China;
      • c. State Key Laboratory of Veterinary Etiological Biology/National Foot and Mouth Disease Reference Laboratory/Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China;
      • d. Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, 66506, USA;
      • e. College of Veterinary Medicine and Virus Vaccine Research Center, Gyeongsang National University, Jinju, 52828, Republic of Korea
      • Received Date: 26 October 2022
      • Accepted Date: 08 March 2023

      Abstract: Foot-and-mouth disease virus (FMDV) has developed various strategies to antagonize the host innate immunity. FMDV Lpro and 3Cpro interfere with type I IFNs through different mechanisms. The structural protein VP3 of FMDV degrades Janus kinase 1 to suppress IFN-γ signaling transduction. Whether non-structural proteins of FMDV are involved in restraining type II IFN signaling pathways is unknown. In this study, it was shown that FMDV replication was resistant to IFN-γ treatment after the infection was established and FMDV inhibited type II IFN induced expression of IFN-γ-stimulated genes (ISGs). We also showed for the first time that FMDV non-structural protein 3C antagonized IFN-γ-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation. 3Cpro expression significantly reduced the ISGs transcript levels and palindromic gamma-activated sequences (GAS) promoter activity, without affecting the protein level, tyrosine phosphorylation, and homodimerization of STAT1. Finally, we provided evidence that 3C protease activity played an essential role in degrading KPNA1 and thus inhibited ISGs mRNA and GAS promoter activities. Our results reveal a novel mechanism by which an FMDV non-structural protein antagonizes host type II IFN signaling.

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