Genistein Targets STING-Driven Antiviral Responses

Cytoplasmic detection of DNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) is an essential component of antiviral responses. Upon synthesis, cGAMP binds to the stimulator of interferon (IFN) genes (STING) in infected and adjacent cells through intercellular transfer by connexins forming gap-junctions, e...

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Published inmBio Vol. 13; no. 4; p. e0206422
Main Authors Ullah, Tomalika R., Balka, Katherine R., Ambrose, Rebecca L., Pépin, Geneviève, Wilce, Matthew C. J., Wilce, Jacqueline A., Thomas, Belinda J., De Nardo, Dominic, Williams, Bryan R. G., Gantier, Michael P.
Format Journal Article
LanguageEnglish
Published 1752 N St., N.W., Washington, DC American Society for Microbiology 30.08.2022
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Summary:Cytoplasmic detection of DNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) is an essential component of antiviral responses. Upon synthesis, cGAMP binds to the stimulator of interferon (IFN) genes (STING) in infected and adjacent cells through intercellular transfer by connexins forming gap-junctions, eliciting a strong IFN-β-driven antiviral response. We demonstrate here that Genistein, a flavonoid compound naturally occurring in soy-based foods, inhibits cGAS-STING antiviral signaling at two levels. First, Genistein pretreatment of cGAMP-producing cells inhibited gap-junction intercellular communication, resulting in reduced STING responses in adjacent cells. In addition, Genistein directly blocked STING activation by the murine agonist DMXAA, by decreasing the interaction of STING with TBK1 and IKKε. As a result, Genistein attenuated STING signaling in human and mouse cells, dampening antiviral activity against Semliki Forest Virus infection. Collectively, our findings identify a previously unrecognized proviral activity of Genistein mediated via its inhibitory effects at two levels of cGAS-STING signaling. IMPORTANCE Several reports suggest that Genistein exhibits antiviral activities against DNA viruses. Our work uncovers a previously unrecognized proviral effect of Genistein, through inhibition of the cGAS-STING pathway at the level of cGAMP transfer and its sensing by STING. This suggests that the use of Genistein as an antiviral should be taken with caution as it may reduce the protective antiviral effects elicited by host STING activation.
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The authors declare a conflict of interest. Michael Gantier is a named inventor of provisional patents relating to cGAS and STING inhibitors.
Present address: Geneviève Pépin, Department of Medical Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Quebec, Canada.
ISSN:2150-7511
2150-7511
DOI:10.1128/mbio.02064-22