Cytosolic DNA-sensing pathway

The cytosolic DNA-sensing pathway is a fundamental innate immune mechanism that detects double-stranded DNA (dsDNA) within the cellular cytoplasm, a location where DNA is typically absent under healthy conditions (KEGG: hsa04623). This pathway primarily involves the enzyme cyclic GMP-AMP synthase (cGAS), which acts as a sensor that, upon binding to dsDNA, catalyzes the production of the second messenger cyclic GMP-AMP (cGAMP) (Science, 2013). cGAMP then activates the stimulator of interferon genes (STING) protein, leading to the recruitment of kinases like TBK1 and the subsequent activation of transcription factors IRF3 and NF-κB (Immunity, 2020). This cascade results in the production of type I interferons and other proinflammatory cytokines, which are essential for antiviral defense and anti-tumor immunity (Nature Reviews Immunology, 2021). Beyond cGAS-STING, other sensors like AIM2 and IFI16 also participate in cytosolic DNA sensing, with AIM2 specifically triggering the assembly of the inflammasome and the release of IL-1β (Journal of Virology, 2015). Dysregulation of these pathways is linked to various diseases, including autoimmune disorders like Aicardi-Goutières syndrome and systemic lupus erythematosus, as well as chronic inflammatory conditions and cancer (Frontiers in Immunology, 2018). Consequently, the pathway is a major focus for drug development, with STING agonists being explored to enhance cancer immunotherapy and cGAS or STING inhibitors being developed to treat autoimmune and inflammatory diseases.

Other names

cGAS-STING pathwayDNA-sensing pathwayAIM2 inflammasome pathwayCytosolic DNA-sensing system

Modulation of innate immune sensors (e.g., cGAS, STING) to either stimulate anti-tumor immunity via type I interferon production or inhibit pathological inflammation in autoimmune and inflammatory diseases.