Cyclic GMP-AMP synthase-Stimulator of interferon genes pathway (cGAS-STING pathway)

The cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway is a fundamental component of the innate immune system that detects the presence of double-stranded DNA (dsDNA) in the cytosol. Under normal conditions, DNA is sequestered within the nucleus or mitochondria; however, the presence of cytosolic DNA—whether from viral or bacterial pathogens, or from damaged self-DNA—triggers cGAS to produce the signaling molecule cGAMP. This second messenger activates STING, initiating a cascade that culminates in the production of type I interferons and pro-inflammatory cytokines, which are essential for mounting an effective immune defense. In oncology, the pathway is a major focus for therapeutic intervention, as STING agonists are being developed to turn 'cold' tumors 'hot' by stimulating anti-tumor T-cell responses. Conversely, chronic or inappropriate activation of the cGAS-STING pathway by self-DNA is a primary driver of various autoinflammatory and autoimmune disorders, such as systemic lupus erythematosus and Aicardi-Goutières syndrome. Consequently, both agonists for cancer immunotherapy and inhibitors for treating inflammatory diseases are currently under intensive clinical and preclinical investigation (Source: PubMed PMID: 30718910, 31110339).

Other names

cGAS-STING signaling axisMB21D1-TMEM173 pathwayDNA-sensing pathwayCyclic guanosine monophosphate-adenosine monophosphate synthase-Stimulator of interferon genes pathway

The cGAS enzyme functions as a cytosolic DNA sensor that, upon binding to double-stranded DNA, catalyzes the synthesis of the second messenger cyclic GMP-AMP (cGAMP). cGAMP subsequently binds to the STING protein located on the endoplasmic reticulum membrane, inducing a conformational change that allows STING to translocate to the Golgi apparatus. There, STING recruits and activates TANK-binding kinase 1 (TBK1), which phosphorylates the transcription factor IRF3, leading to its dimerization and nuclear translocation to drive the expression of type I interferons and other immune-related genes (Source: Nature Reviews Immunology, 2019; UniProt Q8N884, Q86WV6).