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

Foot-and-mouth disease virus (FMDV) has developed various strategies to antagonize the host innate immunity. FMDV L-pro and 3C(pro) interfere with type I IFNs through different mechanisms. The structural protein VP3 of FMDV degrades Janus kinase 1 to suppress IFN-gamma 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-gamma treatment after the infection was established and FMDV inhibited type II IFN induced expression of IFN-gamma-stimulated genes (ISGs). We also showed for the first time that FMDV non-structural protein 3C antagonized IFN-gamma-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation. 3C(pro) 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.