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).
Organ Systems
immune-hematologic
integumentary
Pathway Steps
cytosolic dsDNA (viral / mtDNA / micronucleus / LINE-1) → cGAS dsDNA-binding + activation — via sequence-independent binding via 2 DNA strands per cGAS; phase separation at ↑[DNA]. cGAS detects cytosolic DNA regardless of sequence (binding the backbone of two strands), flagging any mislocalized DNA — viral, mitochondrial, micronuclei from genome instability, or LINE-1 retroelements. DNA-induced liquid-liquid phase separation concentrates the reaction; leakage of self-DNA drives interferonopathies (e.g. AGS) and aging-associated inflammation.
cGAS active + ATP + GTP → 2′3′-cGAMP (unique cyclic dinucleotide) — via distinct from bacterial 3′3′-cGAMP / c-di-GMP / c-di-AMP. Activated cGAS makes 2′3′-cGAMP, a cyclic dinucleotide whose mixed 2′-5′/3′-5′ linkage distinguishes it from bacterial 3′3′ CDNs. cGAMP is the second messenger; the ectoenzyme ENPP1 degrades it — an emerging cancer-immunotherapy target, since clearing cGAMP dampens antitumor immunity.
2′3′-cGAMP → STING (ER) oligomerization + activation — via binds STING-CTD; intercellular 2′3′-cGAMP transfer via gap junctions / virions enables bystander activation. cGAMP binds the STING C-terminal domain and triggers oligomerization. Strikingly, cGAMP can transfer between cells (gap junctions, viral particles, vesicles), letting a sensing cell alert neighbors — and STING gain-of-function mutations cause the autoinflammatory disease SAVI.
STING active → ER → ER-Golgi intermediate → Golgi translocation — via COPII-mediated; ARF1/SAR1 dependent; H-151 blocks this step (covalent palmitoylation site). Activated STING traffics from ER through the ERGIC to the Golgi (COPII/ARF1-dependent) — a relocation required for downstream signaling and the step blocked by the covalent inhibitor H-151. STING is then degraded (lysosomal) after signaling, giving built-in shutoff.
STING (Golgi) → TBK1 recruitment + activation — via STING-CTT binds TBK1 dimer → trans-autophosphorylation. At the Golgi, STING’s C-terminal tail recruits the kinase TBK1, which trans-autophosphorylates. STING acts as a scaffold concentrating TBK1 — the convergence point shared with other innate-immune DNA/RNA-sensing adaptors (MAVS, TRIF) that also signal through TBK1.
TBK1 → IRF3 Ser396 phosphorylation — via dimerization → nuclear translocation → IFN-β + ISG transcription. TBK1 phosphorylates IRF3 (Ser396), driving dimerization and nuclear entry to transcribe type-I interferon (IFN-β) and interferon-stimulated genes — the antiviral/antitumor output that STING agonists aim to harness for cancer immunotherapy.
STING active → NF-κB activation (parallel branch) — via TRAF6 / IKK → pro-inflammatory cytokine output. In parallel, STING activates NF-κB (via TRAF6/IKK) for pro-inflammatory cytokines — so the pathway yields both interferon and inflammatory outputs. The balance between the IRF3/IFN and NF-κB arms shapes whether cGAS-STING drives protective immunity or chronic inflammation/autoimmunity.