Yang, Y.L., Cao, L.B., He, W.R., Zhong, L., Guo, Y., Yang, Q., Shu, H.B., and Hu, M.M.* (2022). Endocytosis triggers V-ATPase-SYK-mediated priming of cGAS activation and innate immune response. Proc Natl Acad Sci U S A 119, e2207280119.（胡明明）

Abstract

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.

全文链接请见：

https://www.pnas.org/doi/10.1073/pnas.2207280119?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed