3Cpro of foot-and-mouth disease virus antagonizes the interferon signaling pathway by blocking STAT1/STAT2 nuclear translocation.

UNLABELLED:Foot-and-mouth disease virus (FMDV) causes a highly contagious, debilitating disease in cloven-hoofed animals with devastating economic consequences. To survive in the host, FMDV has evolved to antagonize the host type I interferon (IFN) response. Previous studies have reported that the leader proteinase (L(pro)) and 3C(pro) of FMDV are involved in the inhibition of type I IFN production. However, whether the proteins of FMDV can inhibit type I IFN signaling is less well understood. In this study, we first found that 3C(pro) of FMDV functioned to interfere with the signaling pathway. Expression of 3C(pro) significantly reduced the transcript levels of IFN-stimulated genes (ISGs) and IFN-stimulated response element (ISRE) promoter activity. The protein level, tyrosine phosphorylation of and and their heterodimerization were not affected. However, the nuclear translocation of was blocked by the 3C(pro) protein. Further mechanistic studies demonstrated that 3C(pro) induced proteasome- and caspase-independent protein degradation of karyopherin α1 the nuclear localization signal receptor for tyrosine-phosphorylated but not karyopherin α2, α3, or α4. Finally, we showed that the protease activity of 3C(pro) contributed to the degradation of and thus blocked duanyu18131/duanyu18132 nuclear translocation. Taken together, results of our experiments describe for the first time a novel mechanism by which FMDV evolves to inhibit IFN signaling and counteract host innate antiviral responses. IMPORTANCE:We show that 3C(pro) of FMDV antagonizes the JAK-duanyu1813 signaling pathway by blocking duanyu18131/duanyu18132 nuclear translocation. Furthermore, 3C(pro) induces Kduanyu15351 degradation, which is independent of proteasome and caspase pathways. The protease activity of 3C(pro) contributes to the degradation of Kduanyu15351 and governs the ability of 3C(pro) to inhibit the JAK-duanyu1813 signaling pathway. This study uncovers a novel mechanism evolved by FMDV to antagonize host innate immune responses.

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