cGAS senses DNA in the cytosol, regardless of its source. Upon binding to DNA, cGAS forms dimers and higher-order oligomers and becomes catalytically active. cGAS produces the RNA-based second messenger 2'3'-cGAMP, which can bind to and activate the downstream effector protein STING. Alternatively, STING can be activated by second messengers produced in bacteria, such as 3'3'-c-di-AMP or 3'3'-c-di-GMP. Upon cyclic-di-nucleotide binding, STING traffics to the Golgi where it oligomerizes and potentiates downstream signaling by inducing the phosphorylation of TBK1, IRF, and IKK, leading to the activation of the transcription factors IRF3 and NF-B and subsequent induction of pro-inflammatory genes. STING activation can also induce autophagy.
