Middle east respiratory syndrome coronavirus ORF8b accessory protein suppresses type I IFN expression by impeding HSP70-dependent activation of IRF3 kinase IKK«

Lok Yin Roy Wong, Zi Wei Ye, Pak Yin Lui, Xuyang Zheng, Shuofeng Yuan, Lin Zhu, Sin Yee Fung, Kit San Yuen, Kam Leung Siu, Man Lung Yeung, Zongwei CAI, Patrick Chiu Yat Woo, Kwok Yung Yuen, Chi Ping Chan*, Dong Yan Jin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human coronavirus causing severe disease and mortality. MERS-CoV infection failed to elicit robust IFN response, suggesting that the virus might have evolved strategies to evade host innate immune surveillance. In this study, we identified and characterized type I IFN antagonism of MERS-CoV open reading frame (ORF) 8b accessory protein. ORF8b was abundantly expressed in MERS-CoV-infected Huh-7 cells. When ectopically expressed, ORF8b inhibited IRF3-mediated IFN-b expression induced by Sendai virus and poly(I:C). ORF8b was found to act at a step upstream of IRF3 to impede the interaction between IRF3 kinase IKK« and chaperone protein HSP70, which is required for the activation of IKK« and IRF3. An infection study using recombinant wild-type and ORF8b-deficient MERS-CoV further confirmed the suppressive role of ORF8b in type I IFN induction and its disruption of the colocalization of HSP70 with IKK«. Ectopic expression of HSP70 relieved suppression of IFN-b expression by ORF8b in an IKK«-dependent manner. Enhancement of IFN-b induction in cells infected with ORF8b-deficient virus was erased when HSP70 was depleted. Taken together, HSP70 chaperone is important for IKK« activation, and MERS-CoV ORF8b suppresses type I IFN expression by competing with IKK« for interaction with HSP70.

Original languageEnglish
Pages (from-to)1564-1579
Number of pages16
JournalJournal of Immunology
Volume205
Issue number6
DOIs
Publication statusPublished - 15 Sep 2020

Scopus Subject Areas

  • Immunology and Allergy
  • Immunology

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