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

Yijun Du, Jingshan Bi, Jiyu Liu, Xing Liu, Xiangju Wu, Ping Jiang, Dongwan Yoo, Yongguang Zhang, Jiaqiang Wu, Renzhong Wan, Xiaomin Zhao, Lihui Guo, Wenbo Sun, Xiaoyan Cong, Lei Chen, Jinbao Wang

Research output: Contribution to journalArticle

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 (Lpro) and 3Cpro 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 3Cpro of FMDV functioned to interfere with the JAK-STAT signaling pathway. Expression of 3Cpro 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 3Cpro protein. Further mechanistic studies demonstrated that 3Cpro 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 3Cpro 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.

Original languageEnglish (US)
Pages (from-to)4908-4920
Number of pages13
JournalJournal of virology
Volume88
Issue number9
DOIs
StatePublished - May 2014

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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