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.

环状GMP-AMP合成酶（cGAS）识别病毒或内源性DNA，以激活感染和自身免疫疾病的固有免疫反应。在结合双链DNA后，cGAS合成2′3′cGMP-AMP，进而触发I型干扰素和促炎细胞因子的产生。除了在细胞质和细胞核中的细胞定位外，cGAS亦存在于质膜上，但其膜定位的功能意义及调控机制尚不明确。在本研究中，我们报告了一些cGAS通过结合MYO1F定位于质膜。在病毒感染后，MYO1F在特定位点上的SYK介导的磷酸化促进了乙酰转移酶KAT2A的募集，该酶进一步在质膜上的赖氨酸残基421、292和131处乙酰化cGAS，而这种乙酰化对于其完全活化至关重要。此外，我们揭示了cGAS的膜定位对于由膜包裹的细胞器释放Mn2+到细胞质中引发的病毒-细胞融合触发的信号激活和I型干扰素产生至关重要。我们的研究结果表明，MYO1F介导的cGAS膜定位对于其应对病毒感染和病毒-细胞融合的完全活化至关重要。