Middle East respiratory syndrome coronavirus ORF4b protein targets cGAS-STING pathway of nucleic acid sensing
Sin-Yee Fung1, Chi-Ping Chan1, Lin Zhu2, Kwok-Yung Yuen3, Patrick C.-Y. Woo3, Zong Wei Cai2 and Dong-Yan Jin1*
1School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong; 2State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Kowloon Tong, Hong Kong; 3Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong
Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human coronavirus that causes severe respiratory disease with a fatality rate of 35%. Potent type I interferon (IFN) induction is prevented in MERS-CoV-infected tissues and patients, suggesting that immune evasion may play a major role in MERS-CoV pathogenesis. Previous studies have shown that MERS-CoV ORF4b antagonizes the activation of type I IFN production in response to the sensing of cytosolic RNA. However, recent studies revealed that some RNA viruses such as Dengue virus could also activate DNA sensing by inducing the leakage of mitochondrial DNA into the cytosol. How infection with MERS-CoV might affect DNA sensing remains to be understood. In this study, we demonstrate suppression of DNA-induced type I IFN response by MERS-CoV ORF4b protein. Expression of MERS-CoV ORF4b protein suppressed type I IFN expression in response to overexpression of cytosolic DNA sensor cGAS and its adaptor STING. This suppressive effect was further confirmed by administration of noncanonical cGAMP, the second messenger in cGAS-STING signaling. Using mass spectrometry, a drop in cGAMP level is observed in ORF4b-overexpressing cell. Mechanistically, ORF4b interacts with cGAS and reduces cGAMP production. ORF4b is known to be capable of degrading 2'-5' oligoadenylate (2'-5' A), but an ORF4b mutant that cannot degrade 2'-5' A was found to have no cGAMP-reducing activity. Taken together, our findings suggest an unrecognized role of the cGAS-STING pathway of cytosolic DNA sensing in MERS-CoV infection, which is perturbed by its ORF4b. Further studies are underway to determine how cGAS-STING pathway might be activated and what could be the ligand of cGAS in the first place in MERS-CoV-infected cells.
This work was supported by the RGC Theme-based Research Scheme (T11-707/15-R).