Cytoplasmic detection of DNA by cyclic GMP–AMP (cGAMP) synthase (cGAS) is an essential component of antiviral responses. Upon synthesis, cGAMP binds to stimulator of interferon (IFN) genes (STING) in infected and adjacent cells, through intercellular transfer by connexin forming gap-junctions, eliciting a strong antiviral response through production of IFN-β. We demonstrate here that Genistein, a flavonoid compound naturally occurring in soy-based foods, inhibits cGAS-STING antiviral signaling at two levels. First, Genistein pre-treatment 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, resulting in dampened STING, TBK1, IKKε and IRF3 phosphorylation. As a result, Genistein attenuated STING signaling in human and mouse cells, resulting in decreased antiviral activity against Semliki Forest Virus infection. Collectively, our findings identify a previously unrecognized pro-viral activity of Genistein mediated via inhibitory effects at two levels of cGAS-STING signaling.
Several reports suggest that Genistein exhibits antiviral activities against DNA viruses. Our findings suggest 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.