MYO1F Positions cGAS on the Plasma Membrane to Ensure Full and Functional Signaling

Cyclic GMP–AMP synthase (cGAS) recognizes viral or endogenous DNA to activate the innate immune response to infection and autoimmune diseases. After binding double-stranded DNA, cGAS synthesizes 2′3′ cGMP–AMP, which triggers the production of type I interferons and proinflammatory cytokines. In addition to its cellular localization in the cytosol and nucleus, cGAS is also present in the plasma membrane, but the functional significance and regulatory mechanism of its membrane localization are still unclear. Here, we report that some cGAS localizes to the plasma membrane by binding to MYO1F. Upon viral infection, SYK-mediated MYO1F phosphorylation at specific sites promotes the recruitment of acetyltransferase KAT2A, which further acetylates cGAS at lysine residues 421, 292, and 131 on the plasma membrane, and this acetylation is essential for its full activation. In addition, we showed that the membrane localization of cGAS is critical for virus‒cell fusion-triggered signalling activation and type I interferon production due to Mn2+ release from membrane-enclosed organelles into the cytosol. Our results show that MYO1F-mediated cGAS membrane localization is critical for its full activation in response to viral infection and virus‒cell fusion.