A conserved methyltransferase active site residue of Zika virus NS5 is required for the restriction of STING activation and interferon expression

Zika virus (ZIKV) is a re- emerging RNA virus and causes major public health events due to its link to severe neurological complications in foetuses and neonates. The cGAS-STING signalling pathway regulates innate immunity and plays an important role in the invasion of DNA and RNA viruses. This study reveals a distinct mechanism by which ZIKV restricts the cGAS-STING signalling to repress IFN-fl expression. ZIKV attenuates IFN-fl expression induced by DNA viruses (herpes simplex virus type 1, HSV- 1) or two double- stranded DNAs (dsDNA90 and HSV120) in mouse embryonic fibroblasts (MEFs). Notably, ZIKV NS5, the viral RNA- dependent RNA polymerase, was responsible for the repression of IFN-fl. NS5 interacts with STING in the cytoplasm, suppresses IRF3 phosphorylation and nucleus localization and promotes the cleavage of STING K48- linked polyubiquitination. Furthermore, the NS5 methyltransferase (MTase) domain interacts with STING to restrict STING- induced IFN-fl expression. Interestingly, point mutation analyses of conserved methyltransferase active site residue D146 indicate that it is critical for repressing IFN-fl expression induced by STING stimulation in cGAS-STING signalling.