title: 3Cpro of foot-and-mouth disease virus antagonizes the interferon signaling pathway by blocking STAT1/STAT2 nuclear translocation.
abstract: 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 JAK-STAT 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 STAT1 and STAT2, and their heterodimerization were not affected. However, the nuclear translocation of STAT1/STAT2 was blocked by the 3C(pro) protein. Further mechanistic studies demonstrated that 3C(pro) induced proteasome- and caspase-independent protein degradation of karyopherin α1 (KPNA1), the nuclear localization signal receptor for tyrosine-phosphorylated STAT1, but not karyopherin α2, α3, or α4. Finally, we showed that the protease activity of 3C(pro) contributed to the degradation of KPNA1 and thus blocked STAT1/STAT2 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.
  
  
  OBJECTIVE
  We show that 3C(pro) of FMDV antagonizes the JAK-STAT signaling pathway by blocking STAT1/STAT2 nuclear translocation. Furthermore, 3C(pro) induces KPNA1 degradation, which is independent of proteasome and caspase pathways. The protease activity of 3C(pro) contributes to the degradation of KPNA1 and governs the ability of 3C(pro) to inhibit the JAK-STAT signaling pathway. This study uncovers a novel mechanism evolved by FMDV to antagonize host innate immune responses.
authors.affiliation: Shandong Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Du
authors.forename: Jingshan
authors.initials: J
authors.lastname: Bi
authors.forename: Jiyu
authors.initials: J
authors.lastname: Liu
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Xiangju
authors.initials: X
authors.lastname: Wu
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.forename: Dongwan
authors.initials: D
authors.lastname: Yoo
authors.forename: Yongguang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Wu
authors.forename: Renzhong
authors.initials: R
authors.lastname: Wan
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhao
authors.forename: Lihui
authors.initials: L
authors.lastname: Guo
authors.forename: Wenbo
authors.initials: W
authors.lastname: Sun
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Cong
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Jinbao
authors.initials: J
authors.lastname: Wang
mesh_terms: D000086042:3C Viral Proteases; D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D029544:Foot-and-Mouth Disease Virus / Q000276:immunology*; D054884:Host-Pathogen Interactions; D007372:Interferons / Q000037:antagonists & inhibitors*; D059748:Proteolysis; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors*; D050795:STAT2 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D013552:Swine; D014764:Viral Proteins / Q000378:metabolism*; D028901:alpha Karyopherins / Q000378:metabolism
chemical_list: D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D014764:Viral Proteins; D028901:alpha Karyopherins; D007372:Interferons; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases