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Volume 38 Issue 3
June 2023
    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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    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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      10.1016j.virs.2023.03.003-ESM.docx

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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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