Category: immune_innate
cGAS-STING is the cytosolic dsDNA sensor that triggers type I interferon (IFN-α/β) — central to antiviral defense, tumor immunogenicity, and several autoinflammatory diseases. Mechanism: cytosolic dsDNA (viral, mitochondrial leakage, micronuclei from genome instability, retroelements like LINE-1) → cGAS (cyclic GMP-AMP synthase) binds dsDNA in a sequence-independent manner → conformational change → synthesizes 2′3′-cGAMP (a unique cyclic dinucleotide). 2′3′-cGAMP binds STING (TMEM173) at the ER → STING oligomerization + translocation to ER-Golgi intermediate → recruits TBK1 → TBK1 phosphorylates IRF3 + STING-CTT → IRF3 dimerization + nuclear translocation → IFN-β + ISG transcription. Parallel: STING also activates NF-κB → pro-inflammatory cytokines. Disease relevance: STING gain-of-function = STING-associated vasculopathy of infancy (SAVI); cGAS gain-of-function and TREX1 loss-of-function (cytosolic DNA hyperaccumulation) = Aicardi-Goutières syndrome; tonic cGAS-STING activation contributes to SLE, lupus nephritis. Tumor immunology: radiotherapy + chemotherapy induce micronuclei → cGAS activation → tumor immunogenicity (Deng 2014); STING agonists (ADU-S100, MK-1454) trialed but disappointing. Inhibitors: H-151, hydroxychloroquine + chloroquine block lysosomal/endosomal DNA pathways and indirectly dampen STING; JAK1/2 inhibitors block downstream IFN signaling. Cross-links: [[tlr_innate_signaling]] (parallel innate-immune branch), [[nfkb_signaling]] (parallel STING output), [[jak_stat_signaling]] (downstream IFN signaling).