West Nile virus NS1 antagonizes interferon beta production by targeting RIG-I and MDA5

Hong Lei Zhang, Han Qing Ye, Si Qing Liu, Cheng Lin Deng, Xiao Dan Li, Pei Yong Shi, Bo Zhang

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


West Nile virus (WNV) is a mosquito-borne flavivirus that causes epidemics of encephalitis and viscerotropic disease worldwide. This virus has spread rapidly and has posed a significant public health threat since the outbreak in New York City in 1999. The interferon (IFN)-mediated antiviral response represents an important component of virus-host interactions and plays an essential role in regulating viral replication. Previous studies have suggested that multifunctional nonstructural proteins encoded by flaviviruses antagonize the host IFN response via various means in order to establish efficient viral replication. In this study, we demonstrated that the nonstructural protein 1 (NS1) of WNV antagonizes IFN-β production, most likely through suppression of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) activation. In a dual-luciferase reporter assay, WNV NS1 significantly inhibited the activation of the IFN-β promoter after Sendai virus infection or poly(I·C) treatment. NS1 also suppressed the activation of the IFN-β promoter when it was stimulated by interferon regulatory factor 3 (IRF3)/5D or its upstream molecules in the RLR signaling pathway. Furthermore, NS1 blocked the phosphorylation and nuclear translocation of IRF3 upon stimulation by various inducers. Mechanistically, WNV NS1 targets RIG-I and melanoma differentiation-associated gene 5 (MDA5) by interacting with them and subsequently causing their degradation by the proteasome. Furthermore, WNV NS1 inhibits the K63-linked polyubiquitination of RIG-I, thereby inhibiting the activation of downstream sensors in the RLR signaling pathway. Taken together, our results reveal a novel mechanism by which WNV NS1 interferes with the host antiviral response.

Original languageEnglish (US)
Article numbere02396-16
JournalJournal of virology
Issue number18
StatePublished - Sep 1 2017


  • Flavivirus
  • IFN-β
  • MDA5
  • NS1
  • RIG-I
  • West Nile virus

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology


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