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 intracel-lular sensors to nucleic acids is sufficient for their activation. Here, we report that endo-cytosis 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 acti-vated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation. Upon binding to DNA, the primed cGAS initiates robust cGAMP produc-tion 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 activa-tion and innate immune response.

Automated summary

The current understanding of nucleic acid-mediated innate immunity is that the binding of intracellular sensors to nucleic acids is enough to activate them. However, this study reveals that the endocytosis of viruses or foreign DNA provides a priming signal for the activation of the DNA sensor cGAS in the innate immune response. This finding demonstrates that the activation of cGAS following endocytosis requires tyrosine phosphorylation mediated by the V-ATPase-SYK pathway.