Figure 2.

Mechanism of cGAS-STING activation

cGAS senses the aberrantly located dsDNAs and is activated to form the homogeneous dimers. The activated cGAS dimers catalyze cGAMP production from ATP and GTP. cGAMP binds to STING to facilitate its translocation from the ER to the Golgi apparatus to recruit TBK1 for autophosphorylation. The phosphorylated TBK1 subsequently induces phosphorylation and dimerization of IRF3, and NF-κB activation, which results in their nuclear trafficking. Nucleic IRF3 and NF-κB trigger the production of IFN-I. The secreted IFN-I binds to the cognate receptor IFNAR to induce the production of interferon-stimulated genes (ISGs). Released cGAMP can be transported through the intercell gap junction and internalized by bystander cells for STING activation, which is important to maintain anti-tumor and anti-viral immunity. Certain bacteria may secret CDNs that resemble the structure of cGAMP to induce activation of STING-TBK1-IRF3/NF-κB axis.