Endocytosis triggers V-ATPase-SYK-mediated priming of cGAS activation and innate immune response.
Yu-Lin YangLi-Bo CaoWen-Rui HeLi ZhongYi GuoQing YangHong-Bing ShuMing-Ming HuPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- immune response
- tyrosine kinase
- nucleic acid
- circulating tumor
- dendritic cells
- cell free
- single molecule
- epidermal growth factor receptor
- toll like receptor
- genome wide
- endothelial cells
- poor prognosis
- dna methylation
- protein kinase
- high glucose
- pseudomonas aeruginosa
- escherichia coli
- biofilm formation
- gene expression
- diabetic rats
- long non coding rna
- inflammatory response
- candida albicans
- genome wide analysis