Suppression of type I interferon production by Middle East respiratory syndrome coronavirus ORF8b accessory protein through interaction with HSP70 chaperone

Identification: Jin, Dong-Yan


Description

 

Suppression of type I interferon production by Middle East respiratory syndrome coronavirus ORF8b accessory protein through interaction with HSP70 chaperone
 
Lok-Yin Roy Wong1, Zi-Wei Ye2, Pak-Yin Lui1, Kam-Leung Siu1, Man-Lung Yeung2, Kit-San Yuen1, Sin-Yee Fung1, Chi-Ping Chan1, Zongwei Cai3, Patrick Chiu-Yat Woo2, Kwok-Yung Yuen2 and Dong-Yan Jin1,*  
1School of Biomedical Sciences, The University of Hong Kong, Hong Kong; 2State Key Lab of Emerging Infectious Diseases and Dept of Microbiology, The University of Hong Kong, Hong Kong; 3State Key Lab of Environmental and Biological Analysis and Dept of Chemistry, Hong Kong Baptist University, Hong Kong
*Corresponding Author
 
Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human pathogen causing severe morbidity and mortality since its identification in 2012. Recurrent and ongoing outbreaks in the Arabian Peninsula and occasional spread to other parts of the world have been reported. Why its infection causes severe diseases and whether this can be accounted for by innate immune evasion remain to be understood. In this study we demonstrate suppression of type I IFN production by MERS-CoV accessory protein ORF8b. ORF8b was found to be abundantly expressed in infected cells. Expression of ORF8b to a level similar to that in infected cells inhibited type I IFN production activated by poly (I:C) or Sendai virus. The inhibitory effect was specific to IRF3 and ORF8b had no influence on NF-κB activation. The levels of phospho-TBK1 and phospho-IRF3 were diminished when ORF8b was overexpressed. An interaction between chaperone protein HSP70-1A and ORF8b was initially identified by mass spectrometry and further verified by co-immunoprecipitation. As molecular chaperones for protein folding and refolding, heat shock proteins (HSPs) are known to be capable of modulating IRF3 phosphorylation. Indeed, HSP70-1A was found to interact with IKK and ectopic expression of HSP70-1A relieved suppression of IFN-β production by ORF8b in an IKK-dependent manner. Finally, an ORF8b-defective MERS-CoV was constructed and found to induce IFN-β more robustly. Taken together, our findings are consistent with a model in which MERS-CoV ORF8b sequesters cellular HSP701A by direct interaction leading to inhibition of IKK-dependent phosphorylation of IRF3 and consequent induction of type I IFN production. Our work has implications in the design of antivirals and vaccines.      
 
Funding
Supported by HKRGC (T11-707/15-R).
 

 

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