Innate DNA-sensing pathways

Innate DNA-sensing pathways are critical components of the immune system that detect the presence of double-stranded DNA (dsDNA) in inappropriate cellular compartments, such as the cytoplasm or endosomes [1: Paludan & Bowie, 2013, Immunity]. The most prominent pathway involves the enzyme cyclic GMP-AMP synthase (cGAS), which detects cytosolic DNA and produces the second messenger cGAMP to activate the Stimulator of Interferon Genes (STING) protein [2: Sun et al., 2013, Science]. Other sensors include Toll-like receptor 9 (TLR9) in endosomes and the AIM2 inflammasome, which triggers pyroptosis [3: Hornung et al., 2009, Nature]. These pathways trigger the production of type I interferons and pro-inflammatory cytokines to combat viral and bacterial infections [4: Barber, 2015, Nature Reviews Immunology]. Dysregulation of these pathways is linked to autoimmune disorders like systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS), while their pharmacological activation is being explored as a potent strategy in cancer immunotherapy to enhance anti-tumor immunity [5: Motwani et al., 2019, Nature Reviews Genetics; 6: Corrales et al., 2015, Cell Reports].

Other names

Cytosolic DNA-sensing pathwaysDNA-sensing immune pathwaysNucleic acid sensingcGAS-STING pathwayTLR9 signaling pathwayAIM2 inflammasome pathway

Modulation of pattern recognition receptors (PRRs) that detect double-stranded DNA, leading to the regulation of type I interferon and pro-inflammatory cytokine production via downstream signaling cascades such as the cGAS-STING, TLR9, or AIM2 pathways.