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 journalArticle

11 Citations (Scopus)

Abstract

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
Volume91
Issue number18
DOIs
StatePublished - Sep 1 2017

Fingerprint

interferon-beta
West Nile virus
Interferon-beta
retinoic acid
melanoma
Tretinoin
Interferons
Melanoma
interferons
Interferon Regulatory Factor-3
Flavivirus
Genes
genes
proteins
Antiviral Agents
Arbovirus Encephalitis
Sendai virus
virus replication
Viral Structures
Proteins

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Zhang, H. L., Ye, H. Q., Liu, S. Q., Deng, C. L., Li, X. D., Shi, P-Y., & Zhang, B. (2017). West Nile virus NS1 antagonizes interferon beta production by targeting RIG-I and MDA5. Journal of Virology, 91(18), [e02396-16]. https://doi.org/10.1128/JVI.02396-16

West Nile virus NS1 antagonizes interferon beta production by targeting RIG-I and MDA5. / Zhang, Hong Lei; Ye, Han Qing; Liu, Si Qing; Deng, Cheng Lin; Li, Xiao Dan; Shi, Pei-Yong; Zhang, Bo.

In: Journal of Virology, Vol. 91, No. 18, e02396-16, 01.09.2017.

Research output: Contribution to journalArticle

Zhang, Hong Lei ; Ye, Han Qing ; Liu, Si Qing ; Deng, Cheng Lin ; Li, Xiao Dan ; Shi, Pei-Yong ; Zhang, Bo. / West Nile virus NS1 antagonizes interferon beta production by targeting RIG-I and MDA5. In: Journal of Virology. 2017 ; Vol. 91, No. 18.
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AB - 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.

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