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GMP-AMP合酶（Cyclic GMP–AMP synthase, cGAS）可识别病毒源性或内源性DNA，从而激活针对感染与自身免疫病的固有免疫应答。在结合双链DNA后，cGAS会合成2′3′-环GMP-AMP（2′3′ cGMP–AMP），后者可诱导I型干扰素与促炎细胞因子的产生。除定位于细胞质基质与细胞核外，cGAS还可存在于细胞质膜，但其膜定位的功能意义与调控机制目前仍不明确。本研究发现，部分cGAS可通过结合肌球蛋白1F（MYO1F）定位于细胞质膜。在病毒感染过程中，脾酪氨酸激酶（Spleen tyrosine kinase, SYK）介导MYO1F的特定位点磷酸化，进而招募乙酰转移酶KAT2A（acetyltransferase KAT2A）；该酶可进一步在细胞质膜上对cGAS的赖氨酸残基421、292与131进行乙酰化修饰，而这一乙酰化修饰对于cGAS的完全激活至关重要。此外，本研究还证实，由于膜包被细胞器释放的锰离子（Mn²+）进入细胞质基质，cGAS的膜定位对于病毒-细胞融合触发的信号通路激活与I型干扰素产生均具有关键作用。本研究结果表明，MYO1F介导的cGAS膜定位，在cGAS应对病毒感染与病毒-细胞融合的完全激活过程中发挥着关键作用。