Seneca Valley virus 3Cpro antagonizes type I interferon response by targeting STAT1-STAT2-IRF9 and KPNA1 signals

The Seneca Valley virus (SVV) is an emerging pathogen that causes vesicular disease in pigs, posing a threat to the pork industry. The type I interferon (IFN) signaling pathway is the major defense mechanism of host innate immune responses, and SVV has developed numerous strategies to antagonize the IFN signaling and promote viral replication. However, the molecular mechanisms by which SVV affects IFN signaling components have not been fully elucidated. Here, we revealed that SVV proteinase (3C(pro)) inhibited IFN-alpha signaling by degrading signal transducer and activator of transcription (STAT) 1, STAT2, and interferon regulatory factor 9 (IRF9) through its protease activity, which is dependent on the caspase pathway. 3C(pro) was further found to cleave STAT2 at glutamine 758 (Q758) within the transactivation domain, and the cleaved STAT2 products attenuated its ability to activate IFN-stimulated responsive element activity and induce the production of IFN-stimulated genes. Additionally, 3C(pro) impaired the nuclear import and formation of the IFN-stimulated gene factor 3 complex. 3C(pro) also induced karyopherin 1 degradation to block STAT1/STAT2 nuclear localization. Collectively, SVV 3C(pro) is capable of subverting the type I IFN response by targeting STAT1-STAT2-IRF9 and karyopherin alpha 1 signals, which uncovers a novel mechanism exploited by SVV to evade host type I IFN response for efficient replication.IMPORTANCE Type I interferon (IFN) signaling plays a principal role in host innate immune responses against invading viruses. Viruses have evolved diverse mechanisms that target the Janus kinase-signal transducer and activator of transcription (STAT) signaling pathway to modulate IFN response negatively. Seneca Valley virus (SVV), an emerging porcine picornavirus, has received great interest recently because it poses a great threat to the global pork industry. However, the molecular mechanism by which SVV evades host innate immunity remains incompletely clear. Our results revealed that SVV proteinase (3C(pro)) antagonizes IFN signaling by degrading STAT1, STAT2, and IRF9, and cleaving STAT2 to escape host immunity. SVV 3C(pro) also degrades karyopherin 1 to block IFN-stimulated gene factor 3 nuclear translocation. Our results reveal a novel molecular mechanism by which SVV 3C(pro) antagonizes the type I IFN response pathway by targeting STAT1-STAT2-IRF9 and karyopherin alpha 1 signals, which has important implications for our understanding of SVV-evaded host innate immune responses.