Location: Virus and Prion ResearchTitle: 3Cpro of FMDV inhibits type II interferon-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation
|WU, XIANGJU - Shandong Academy Of Agricultural Sciences|
|CHEN, LEI - Shandong University|
|SIU, CHAO - Shandong Academy Of Agricultural Sciences|
|HU, YUE - Shandong Academy Of Agricultural Sciences|
|JIANG, DANDAN - Shandong Academy Of Agricultural Sciences|
|YANG, FAN - Chinese Academy Of Agricultural Sciences|
|LI, JUNTONG - Shandong Academy Of Agricultural Sciences|
|CONG, XIAOYAN - Shandong Academy Of Agricultural Sciences|
|HRABCHENKO, NATALIIA - Shandong Academy Of Agricultural Sciences|
|LEE, CHANGHEE - Gyeongsang National University|
|DU, YIJUN - Shandong Agricultural University|
|QI, JING - Shandong Agricultural University|
Submitted to: Virologica Sinica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/14/2023
Publication Date: 6/20/2023
Citation: Wu, X., Chen, L., Siu, C., Hu, Y., Jiang, D., Li, D., Miller, L.C., Li, J., Cong, X., Lee, C., Du, Y. 2023. 3Cpro of FMDV inhibits type II interferon-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation. Virologica Sinica. 38(3):387-397. https://doi.org/10.1016/j.virs.2023.03.003.
Interpretive Summary: Foot-and-mouth diseases virus (FMDV) is a picornavirus that causes a significant disease in agricultural animals. FMDV has developed diverse strategies to escape the host interferon response. Here we demonstrate that FMDV infection interferes with the type II IFN signaling pathway and non-structural protein 3C inhibited IFN-'-stimulated inteferon-stimulated-genes (ISGs) mRNA synthesis and gamma-activated sequences (GAS) promoter activity. Moreover, 3Cpro of FMDV antagonizes the type II IFN-stimulated JAK-STAT signaling pathway through blocking the nuclear translocation of STAT1. Finally, FMDV 3C protease activity plays an essential role in degrading karyopherin subunit alpha 1 (KPNA1) and thus inhibits ISGs mRNA and GAS promoter activities. This study uncovers a new mechanism through which FMDV prevents type II IFN signaling and offsets the host innate antiviral response.
Technical Abstract: To survive efficiently, FMDV has evolved strategies to antagonize the host innate immune system. FMDV Lpro and 3Cpro interfere with type I IFNs through different mechanisms. FMDV structural protein VP3 degrades Janus kinase 1 to suppress IFN-' signal transduction pathways. Whether FMDV non-structural proteins are involved in inhibiting type II IFN signaling is unknown. In this study, we showed that FMDV replication was resistant to IFN-' treatment after the infection was established and FMDV inhibited type II IFN induction of IFN-'-stimulated genes (ISGs) expression. We also showed for the first time that FMDV non-structural protein 3C antagonized IFN-'-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation. Expression of 3Cpro significantly reduced the transcript levels of ISGs and palindromic gamma-activated sequences (GAS) promoter activity. The protein level, tyrosine phosphorylation of STAT1 and its homodimerization were not influenced. Finally, we provide evidence that 3C protease activity plays an essential role in degrading KPNA1 and thus inhibits ISGs mRNA and GAS promoter activities by increasing KPNA1 expression level. Results of our study reveal a novel mechanism developed by an FMDV non-structural protein to antagonize host type II IFN signaling.