Condensation of cGAS induced by Tyr242 phosphorylation and interaction with MYL6 mediates vascular innate immunity in the lung.

An uncontrolled innate immune response to pathogens in the lung causes acute lung injury, in which the cytosolic double-stranded DNA (dsDNA) sensor, cyclic GMP-AMP synthase (cGAS), and its induction of interferon-β (IFN-β) play a crucial role. Given that the vascular endothelium is a point of host contact for both environmental and blood-borne pathogens, we investigated the response of cGAS to dsDNA in endothelial cells in regulating innate immunity in the lung. We found that the phosphorylation of Tyr242 of cGAS facilitated an interaction between cGAS and activated myosin light chain 6 (MYL6), enabling cGAS condensation and activation and leading to IFNB mRNA expression. Furthermore, cGAS binding to dsDNA rapidly increased intracellular Ca2+ in a manner requiring the ER Ca2+ sensor STIM1 to activate MYL6 for cGAS condensation. In cGAS-deficient mice, expression of wild-type cGAS or a phosphomimetic cGAS mutant in the lung endothelium was sufficient to enhance signaling downstream of cGAS, induce neutrophil recruitment, and exacerbate lung damage in response to Pseudomonas aeruginosa infection. Our findings suggest a role for phosphorylation of Tyr242 in cGAS in the endothelium as critical for inducing innate immune responses to pathogens and contributing to acute lung injury.