Foot-and-mouth disease virus 3D polymerase antagonizes the interferon signaling pathway by blocking STAT2 nuclear translocation

Foot-and-mouth disease virus (FMDV) is the etiological agent of foot-and-mouth disease (FMD), which is highly contagious and extremely destructive in cloven-hoofed animals. Previous studies have shown that FMDV strongly suppress the innate immune response, and the research mainly focused on FMDV 3C and L proteinase. However, the role of FMDV 3D polymerase, an RNA-dependent RNA polymerase (RdRp), in inhibiting the IFN signaling pathway remains unclear. In this study, for the first time, we demonstrate that the highly conserved 3D polymerase of FMDV inhibits the activation of the JAK-STAT signaling pathway by targeting STAT2. Mechanistically, FMDV 3D significantly inhibits the activity of the interferon-stimulated response element promoter and downregulates the transcription of interferon-stimulated genes. Further research revealed that 3D interacts with STAT2, hinders its phosphorylation, and inhibits its nuclear translocation, thereby blocking the activation of the JAK-STAT signaling pathway. Collectively, these findings elucidate a novel mechanism by which FMDV 3D polymerase, acting as an inhibitor, targets STAT2 to suppress IFN signaling and antagonize the host antiviral immune response. This will provide insights for the development of future anti-FMDV strategies.