Cyclic GMP-AMP (cGAMP) synthase (cGAS) (161-522) is a truncated form of cGAS that contains the nucleotidyltransferase and Mab21 domains. cGAS is a nucleotidyltransferase located in the cytosol that acts as a cytosolic DNA sensor to detect foreign DNA from microbial pathogens as part of the innate immune response. Upon binding to cytosolic DNA, cGAS produces the cyclic dinucleotide second messenger cGAMP, which activates stimulator of interferon genes (STING), leading to activation of the type I interferon (IFN) pathway. In vitro, fibroblasts, macrophages, and dendritic cells isolated from cGAS knockout (cGAS-/-) mice do not produce type I IFNs following DNA transfection or DNA virus infection. Similarly, cells containing a frame-shift mutation in the cGAS locus fail to mount an immune response to HIV and other retroviruses. In vivo, cGAS-/- mice infected with herpes simplex virus 1 (HSV-1) have lower levels of IFN-α and IFN-β, shorter survival times, and higher post-mortem levels of HSV-1 in the brain.
