Foot-and-mouth disease virus VP4 interferes with host interferon response by targeting the nuclear translocation of interferon regulatory factor 3 (IRF3).

Abstract

Upon RNA virus infection, nuclear translocation of activated transcriptional factors via the RNA-sensing signal pathway is a key event in the interferon (IFN)-mediated antiviral response, and a specific target of viral immune evasion. Foot-and-mouth disease virus (FMDV) causes an acute vesicular disease in cloven-hoofed animals and poses a serious economic risk to the dairy industry. FMDV VP4, one of the structural proteins, is an internal protein of the viral capsid and is known to play an important role in cell entry. Here, we demonstrate a novel molecular mechanism by which VP4 inhibits karyopherin (KPNA)-mediated antiviral immune responses. VP4 and IRF3 specifically interacted with the nuclear localization signal (NLS) binding site on the KPNA4 molecule, and VP4 inhibited the interaction between KPNA4 and IRF3 via competitive binding with higher affinity. Thus, VP4 inhibited nuclear translocation of IRF3 without affecting dimerization and phosphorylation of IRF3. Consequently, VP4 significantly enhanced the replication of RNA and DNA viruses by suppressing IFN production through inhibition of the IRF3-mediated type I IFN signaling pathway. Taken together, these results suggest that VP4 negatively regulates host type I IFN signaling by inhibiting the nuclear translocation of IRF3 and provide a critical implication for better understanding the pathogenesis of FMDV.