Endocytosis triggers V-ATPase-SYK-mediated priming of cGAS activation and innate immune response

The current view of nucleic acid-mediated innate immunity is that binding of intracellular sensors to nucleic acids is sufficient for their activation. Here, we report that endocytosis of virus or foreign DNA initiates a priming signal for the DNA sensor Cyclic GMP-AMP Synthase (cGAS)-mediated innate immune response. Mechanistically, viral Infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (Syk) and cGAS to the endosomal vacuolar H⁺ pump (V-ATPase), where Syk is activated and then phosphorylates human cGAS^Y214/215 (mouse cGas^Y200/201) to prime its activation. Upon binding to DNA, the primed cGAS initiates robust cGAMP production and mediator of IRF3 activation/stimulator of interferon genes-dependent innate immune response. Consistently, blocking the V-ATPase-SYK axis impairs DNA virus- and transfected DNA-induced cGAMP production and expression of Antiviral genes. Our findings reveal that V-ATPase-SYK-mediated tyrosine phosphorylation of cGAS following endocytosis of virus or other cargos serves as a priming signal for cGAS activation and innate immune response.

DNA sensor cGAS; antiviral innate immunity; phosphorylation modification; signal transduction.