{"gene":"STING1","run_date":"2026-06-10T07:46:43","timeline":{"discoveries":[{"year":2008,"finding":"STING (TMEM173) was identified as an endoplasmic reticulum-resident adaptor protein with five putative transmembrane regions that activates both NF-κB and IRF3 transcription pathways to induce type I interferon. Loss of STING rendered murine embryonic fibroblasts susceptible to negative-stranded virus infection and abrogated IFN-β induction by intracellular B-form DNA and herpesviruses. Yeast two-hybrid and co-immunoprecipitation showed STING interacts with RIG-I and with SSR2/TRAPβ (a translocon-associated protein), and RNAi ablation of TRAPβ and SEC61β inhibited STING-mediated IFN-β stimulation.","method":"Expression cloning, siRNA knockdown, yeast two-hybrid, co-immunoprecipitation, viral infection assays in MEFs","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — expression cloning with functional loss-of-function, reciprocal co-IP, multiple orthogonal methods; foundational paper replicated across the field","pmids":["18724357"],"is_preprint":false},{"year":2008,"finding":"MITA (STING/TMEM173) was identified as a critical mediator linking virus-sensing receptors to IRF3 activation. It localizes to the outer membrane of mitochondria, associates with VISA (mitochondrial adaptor), interacts with IRF3, and recruits kinase TBK1 to the VISA-associated complex. MITA is phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3.","method":"Expression cloning, knockdown, co-immunoprecipitation, subcellular fractionation/localization, kinase assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, kinase phosphorylation assay, localization, multiple orthogonal methods; independently identified same gene","pmids":["18818105"],"is_preprint":false},{"year":2009,"finding":"The E3 ubiquitin ligase RNF5 interacts with MITA/STING in a viral-infection-dependent manner and targets MITA at Lys150 for K48-linked ubiquitination and proteasomal degradation, thereby negatively regulating virus-triggered IFN signaling. Viral infection causes redistribution of MITA to the ER and RNF5 to mitochondria, and RNF5-mediated ubiquitination and degradation of MITA occurs at the mitochondria.","method":"Co-immunoprecipitation, overexpression/knockdown, ubiquitination assay, viral infection, subcellular fractionation","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific ubiquitination mapped (K150), subcellular localization, multiple orthogonal functional assays in single focused study","pmids":["19285439"],"is_preprint":false},{"year":2014,"finding":"Gain-of-function mutations in TMEM173 (STING) cause constitutive activation of the STING pathway, leading to elevated IFN-β transcription and STAT1 phosphorylation, and result in STING-associated vasculopathy with onset in infancy (SAVI). HEK293T cells transfected with mutant STING constructs showed elevated IFNB1 reporter levels. STING is expressed in endothelial cells and cGAMP stimulation caused endothelial activation and apoptosis. JAK inhibitor treatment reduced constitutive STAT1 phosphorylation in patient lymphocytes.","method":"Candidate gene sequencing, IFNB1 reporter assay in HEK293T cells, cGAMP stimulation of patient fibroblasts/endothelial cells, phospho-STAT1 assay, JAK inhibitor treatment","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays (reporter, primary cells, patient-derived material, pharmacological rescue) establishing gain-of-function mechanism","pmids":["25029335"],"is_preprint":false},{"year":2016,"finding":"Palmitoylation of STING at Cys88/Cys91 at the Golgi is essential for STING activation and induction of type I interferon host defense genes. Palmitoylation inhibitor 2-bromopalmitate (2-BP) suppressed STING palmitoylation and abolished the IFN response. A Cys88/91Ser mutant STING could not induce STING-dependent defense genes. Constitutively active disease-associated STING variants were also inhibited by 2-BP or the Cys88/91Ser mutation.","method":"Palmitoylation inhibitor treatment, site-directed mutagenesis (C88/91S), IFN reporter assay, subcellular localization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific mutagenesis combined with pharmacological inhibition and functional readout; mechanism independently validated with disease mutants","pmids":["27324217"],"is_preprint":false},{"year":2019,"finding":"Cryo-EM structure of human TBK1 in complex with cGAMP-bound full-length chicken STING revealed that the C-terminal tail of STING adopts a β-strand-like conformation and inserts into a groove between the kinase domain of one TBK1 subunit and the scaffold/dimerization domain of the second TBK1 subunit. The phosphorylation site Ser366 in the STING tail cannot reach the kinase active site of bound TBK1, indicating STING phosphorylation requires oligomerization of both proteins. Mutational analyses validated the TBK1-STING interaction mode.","method":"Cryo-EM structural determination, mutational analysis, functional validation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with mutagenesis validation providing atomic-resolution mechanism","pmids":["30842653"],"is_preprint":false},{"year":2019,"finding":"Structural and biochemical analyses showed that 2'3'-cGAMP induces closing of the human STING homodimer and release of the C-terminal tail, exposing a polymerization interface leading to disulfide-linked polymer formation via Cys148. Disease-causing hyperactive STING mutations either flank C148 (depending on disulfide formation) or reside in the C-terminal tail binding site (causing constitutive tail release and polymerization). Bacterial cyclic-di-GMP induces an alternative active conformation and acts as a partial antagonist of 2'3'-cGAMP signaling.","method":"X-ray crystallography, biochemistry (disulfide crosslinking, polymer formation assays), mutagenesis, ligand competition assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biochemical validation, mutagenesis, and mechanistic dissection of multiple ligand effects","pmids":["31230712"],"is_preprint":false},{"year":2018,"finding":"PINK1 and Parkin mitigate STING-dependent inflammation: loss of either PINK1 or Parkin in mice triggered strong inflammatory phenotypes following exhaustive exercise or accumulation of mtDNA mutations, and this inflammation was completely rescued by concurrent loss of STING. The loss of dopaminergic neurons and motor defects in aged Prkn−/−;mutator mice were also rescued by STING loss, indicating that mitophagy restrains innate immunity by limiting STING activation by cytosolic mtDNA.","method":"Double-knockout mouse genetic epistasis (Prkn−/−; Pink1−/−; Sting−/−), behavioral testing, histology, cytokine measurement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo genetic epistasis with multiple phenotypic readouts; replicated across two genetic models (exercise and mutator)","pmids":["30135585"],"is_preprint":false},{"year":2020,"finding":"Cellular redox homeostasis maintained by GPX4 is required for STING activation. GPX4 deficiency enhanced lipid peroxidation, which led to STING carbonylation at Cys88 and inhibited STING trafficking from the ER to the Golgi complex, thereby specifically attenuating the cGAS-STING pathway and promoting HSV-1 replication in vivo.","method":"GPX4 knockout/inhibition, lipid peroxidation assay, STING carbonylation measurement, ER-to-Golgi trafficking assay, in vivo viral infection","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific carbonylation at C88 identified, trafficking phenotype quantified, in vivo validation; multiple orthogonal methods","pmids":["32541831"],"is_preprint":false},{"year":2023,"finding":"Apo-STING forms a bilayer with head-to-head and side-by-side packing mediated by its ligand-binding domain (LBD), which holds two ER membranes together to prevent ER exit and eliminate TBK1 recruitment—representing the autoinhibited state. Upon 2'3'-cGAMP binding, STING adopts a bent monolayer filament assembly mediated by both LBD and transmembrane domain (TMD), which deforms the ER membrane to support ER exit and anterograde transport.","method":"Cryo-EM structural determination of apo and ligand-bound STING assemblies, biochemical assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures of both autoinhibited and active states providing mechanistic understanding of ER exit","pmids":["37086726"],"is_preprint":false},{"year":2023,"finding":"TAK1 kinase is activated by STING in a TAB1-dependent manner prior to STING trafficking and directly phosphorylates STING on Ser355, facilitating interaction of STING with STEEP and promoting STING oligomerization and translocation from the ER to the ERGIC for subsequent activation.","method":"Biochemical kinase assay, phosphorylation site identification, co-immunoprecipitation, genetic knockout, STING trafficking assay, in vivo tumor model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with site mapping (S355), Co-IP for STEEP interaction, trafficking phenotype, in vivo validation","pmids":["37832545"],"is_preprint":false},{"year":2023,"finding":"STING directly interacts with WIPI2 (key protein for LC3 lipidation in autophagy) to induce autophagosome formation. The STING-WIPI2 interaction is necessary for STING-induced autophagosome formation but does not affect STING activation or intracellular trafficking. The interaction competes with PI3P binding to WIPI2, causing mutual inhibition between STING-induced autophagy and canonical PI3P-dependent autophagy. This interaction enables clearance of cytoplasmic DNA and attenuation of cGAS-STING signaling.","method":"Co-immunoprecipitation, mutagenesis, LC3 lipidation assay, autophagosome formation assay, cytoplasmic DNA clearance assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated by Co-IP, competition with PI3P characterized, functional consequences in multiple assays","pmids":["36872914"],"is_preprint":false},{"year":2023,"finding":"NF-κB pathway activation (via TLR, IL-1R, TNFR, GF-R, or PKC signaling) dramatically enhances STING-mediated immune responses by inducing microtubule depolymerization. STING interacts with microtubules, which plays a crucial role in STING intracellular trafficking. NF-κB-induced microtubule depolymerization inhibits STING trafficking to lysosomes for degradation, increasing levels of activated STING. Gain-of-function STING mutations abolish the microtubule-STING interaction causing ligand-independent autoactivation.","method":"Co-immunoprecipitation (STING-microtubule), STING trafficking assay, microtubule depolymerization experiments, gain-of-function mutant analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct STING-microtubule interaction demonstrated, trafficking phenotype quantified, mechanistic validation with gain-of-function mutants; multiple methods","pmids":["36857187"],"is_preprint":false},{"year":2020,"finding":"The deubiquitinase OTUD5 interacts with STING and cleaves its K48-linked polyubiquitin chains, promoting STING stability. Knockout of OTUD5 resulted in faster STING turnover and impaired type I IFN signaling following cytosolic DNA stimulation. Myeloid-specific Otud5 knockout mice showed increased susceptibility to HSV-1 infection and faster melanoma development.","method":"Co-immunoprecipitation, deubiquitination assay (K48 linkage), STING stability/turnover assay, conditional knockout mice, viral infection and tumor models","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — deubiquitination assay with linkage specificity (K48), Co-IP, in vivo knockout phenotype; multiple methods","pmids":["32879469"],"is_preprint":false},{"year":2020,"finding":"RNF115 catalyzes K63-linked ubiquitination of MITA/STING after HSV-1 infection; HSV-1-induced aggregation of MITA was impaired in Rnf115−/− cells. This is distinct from its constitutive K48-linked ubiquitination of MAVS in uninfected cells. Rnf115−/− mice exhibit hyper-sensitivity to HSV-1 infection (consistent with reduced MITA activation) and hypo-sensitivity to EMCV infection.","method":"Knockout mouse, ubiquitination assay (K63 and K48 linkage), Co-immunoprecipitation, viral infection assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — linkage-specific ubiquitination assay, Co-IP, in vivo knockout with dual viral infection phenotype confirming specificity","pmids":["33139700"],"is_preprint":false},{"year":2021,"finding":"STING1 interacts with components of the mTORC1 complex and promotes mTORC1 complex formation under lipotoxic (palmitic acid) conditions in a SQSTM1-dependent manner. STING1 deficiency or rapamycin treatment decreased lipid droplet numbers and restored lipophagy that was inhibited by palmitic acid. Increased mTORC1 activation concomitant with STING1 activation was observed in NAFLD patient liver tissue.","method":"Co-immunoprecipitation (STING1-mTORC1 components), STING1 knockout/knockdown, rapamycin treatment, lipid droplet and lipophagy assays, patient tissue analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP demonstrated STING1-mTORC1 interaction, SQSTM1 dependency tested, functional lipophagy phenotype; single lab but multiple methods","pmids":["34382907"],"is_preprint":false},{"year":2022,"finding":"UXT (ubiquitously expressed prefoldin-like chaperone) interacts with STING1 upon DNA/cGAMP stimulation and promotes STING1 degradation through selective macroautophagy via SQSTM1. UXT facilitates the interaction between SQSTM1 and STING1 for more efficient autophagic degradation. UXT knockout in mice enhanced cGAS-STING1 signaling during DNA-virus infection and in a lupus model.","method":"Co-immunoprecipitation, STING1 degradation assay, autophagy inhibitor experiments, knockout mouse models (viral infection and lupus), patient PBMC analysis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, mechanistic pathway (SQSTM1-mediated autophagy), in vivo knockout phenotype in two disease models; multiple orthogonal methods","pmids":["35543189"],"is_preprint":false},{"year":2024,"finding":"ISGylation of STING at Lys150 by E3 ISGylation ligases HERC5 (human) / HERC6 (mouse) prevents K48-linked ubiquitination and degradation of STING, thereby facilitating STING activation and type I IFN signaling. Herc6 deficiency suppressed HSV-1-induced IFN responses and facilitated viral replication. SARS-CoV-2 papain-like protease cleaves HERC5-mediated ISGylation of STING to suppress host antiviral responses.","method":"ISGylation assay (K150 site mapping), K48 ubiquitination assay, Herc6 knockout mice, viral infection assays, viral protease cleavage assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific ISGylation (K150) identified with competing ubiquitination, in vivo knockout phenotype, viral evasion mechanism validated","pmids":["38652662"],"is_preprint":false},{"year":2025,"finding":"STING-induced noncanonical autophagy (CASM) activates LRRK2 kinase via lipidation of GABARAP at lysosomes. STING activation generates pH-elevated Golgi-derived vesicles leading to ATG16L1/V-ATPase-dependent noncanonical autophagy, MiT/TFE transcription factor activation (through lipidated GABARAP sequestering FNIP-Folliculin from mTORC1), and ALIX-mediated ESCRT recruitment to mitigate endolysosomal perturbation.","method":"STING activation assays, CASM assay, GABARAP lipidation assay, LRRK2 kinase assay, mTORC1 activity measurement, FNIP-Folliculin interaction assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays establishing pathway; single lab, though multiple orthogonal methods","pmids":["39982740"],"is_preprint":false},{"year":2025,"finding":"STING activates LRRK2 kinase via the CASM-GABARAP pathway at lysosomes. STING signaling drives GABARAP lipidation, and LRRK2 lysosome recruitment and kinase activation are highly dependent on interactions with GABARAP. Multiple stimuli that perturb lysosomal homeostasis converge on CASM to activate LRRK2.","method":"STING activation, LRRK2 kinase assay, GABARAP lipidation assay, lysosome recruitment assay, genetic epistasis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase activation assay with GABARAP dependency and STING genetic epistasis; single lab, multiple methods","pmids":["39812709"],"is_preprint":false},{"year":2025,"finding":"STING upregulates ZBP1 and MLKL expression through a transcriptional program, enabling necroptosis via ZBP1-RIPK1-RIPK3 complex formation independently of FADD-RIPK1-RIPK3. In a SAVI mouse model (Sting1N153S), immune-cell-driven pathology and lethality are rescued by Ripk3 co-deletion, establishing STING-driven ZBP1-mediated necroptosis as a central pathogenic mechanism.","method":"Genetic epistasis (Sting1N153S/Ripk3 double mutant mice), ZBP1/MLKL expression assay, complex formation assay (Co-IP), caspase-8 conditional deletion model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo genetic rescue (Ripk3 deletion), complex formation identified, confirmed in human SAVI patient transcriptomics and mouse model","pmids":["40834903"],"is_preprint":false},{"year":2023,"finding":"STING1 has a nuclear function: its cyclic dinucleotide-binding domain interacts with the N-terminal domain of the transcription factor AHR, activating AHR to control gut microbiota composition and intestinal homeostasis. This nuclear function is independent of DNA sensing and autophagy and shows competitive inhibition with cytoplasmic cGAS-STING1 signaling. AHR ligand protection of colitis was abrogated by mutational inactivation of STING1.","method":"Co-immunoprecipitation (STING1-AHR), domain mapping, STING1 nuclear localization assay, STING1 mutant mouse (colitis model), proteomics of nuclear partners","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, in vivo mutant mouse phenotype, proteomics; single lab but multiple orthogonal methods","pmids":["38016467"],"is_preprint":false},{"year":2014,"finding":"NET23/STING (same protein) strongly promotes chromatin compaction from the nuclear envelope. A correlation between chromatin compaction and endogenous NET23/STING levels was found across multiple human cell lines. STING-induced chromatin compaction is associated with changes in histone methylation and acetylation and is independent of apoptosis (compaction persists with Z-VAD treatment).","method":"Chromatin compaction screen (pixel intensity clustering), endogenous level correlation across cell lines, Z-VAD treatment, epigenetic mark analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization/function experiments with multiple cell lines and pharmacological controls; single lab, but multiple methods","pmids":["25386906"],"is_preprint":false},{"year":2011,"finding":"A human MPYS/STING haplotype (HAQ: R71H-G230A-R293Q) exhibits >90% loss of ability to stimulate IFN-β production. The loss of IFNβ activity is primarily due to the R71H and R293Q SNPs. Fibroblasts and macrophages expressing HAQ are defective in Listeria monocytogenes infection-induced IFN-β production.","method":"Human cohort SNP analysis, IFN-β reporter assay, site-directed mutagenesis (individual SNPs), Listeria infection assay in primary cells","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional loss-of-function mapped to specific residues by mutagenesis, validated in primary cells; single lab","pmids":["21248775"],"is_preprint":false},{"year":2013,"finding":"MPYS/STING deficiency leads to increased bacterial burden in the liver upon Listeria monocytogenes infection, correlated with diminished MCP-1/MCP-3 chemokine production and decreased Ly6Chi monocyte frequency in blood and liver. MPYS-deficient Ly6Chi monocytes are intrinsically defective in migration to the liver. Adoptive transfer of wild-type Ly6Chi monocytes into MPYS-deficient mice decreased liver bacterial burden.","method":"MPYS-deficient mouse infection model, adoptive transfer, monocyte migration assay, chemokine measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with multiple phenotypic readouts and adoptive transfer rescue; single lab","pmids":["23378430"],"is_preprint":false},{"year":2024,"finding":"STING physically interacts with PERK (the protein kinase RNA-like ER kinase, an arm of ER stress) in kidney tubule cells, and STING agonists induce PERK activation. Mice with a STING activating mutation presented with ER stress and kidney fibroinflammation. Tubule-specific STING deletion protected mice from ER stress and kidney fibrosis.","method":"Co-immunoprecipitation (STING-PERK), STING agonist treatment, STING activating-mutation mouse model, conditional tubule-specific STING knockout, kidney fibrosis assays","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct STING-PERK interaction by Co-IP, two mouse genetic models (gain-of-function and conditional KO); single lab","pmids":["39566842"],"is_preprint":false},{"year":2021,"finding":"STING1 polymerization is necessary for FMDV (RNA virus)-induced EIF2AK3/PERK-dependent integrated stress response and reticulophagy, independent of STING1 translocation to the Golgi or IFN response activation. Knockdown/knockout of STING1 or EIF2AK3 suppresses FMDV genome replication. FMDV-triggered signaling originates from DDX58/RIG-I which transmits signals to ER-anchored STING1.","method":"Knockout/knockdown of STING1 and EIF2AK3, STING1 polymerization assay, reticulophagy assay, viral replication assay, epistasis with DDX58","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (DDX58→STING1→EIF2AK3), polymerization requirement demonstrated, Golgi-independent mechanism confirmed by translocation-defective mutants; single lab","pmids":["34338134"],"is_preprint":false},{"year":2019,"finding":"HCMV protein UL42 interacts with MITA/STING and impairs MITA translocation from the ER to perinuclear punctate structures (required for MITA activation) by facilitating p62/LC3B-mediated degradation of TRAPβ. UL42 deficiency enhances HCMV-induced type I IFN production and downstream antiviral gene expression, and impairs viral replication.","method":"Co-immunoprecipitation (UL42-MITA), MITA trafficking assay, UL42-deficient HCMV construction, viral replication assay, p62/LC3B-mediated degradation assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct STING interaction, trafficking phenotype, viral genetics; single lab, multiple methods","pmids":["31107917"],"is_preprint":false},{"year":2020,"finding":"HCMV protein UL94 interacts with MITA/STING and disrupts MITA dimerization and translocation, and impairs TBK1 recruitment to the MITA signalosome. UL94 deficiency potentiates HCMV-induced type I IFN transcription and downstream antiviral effectors while impairing viral replication.","method":"Co-immunoprecipitation (UL94-MITA), MITA dimerization assay, translocation assay, TBK1 recruitment assay, UL94-deficient HCMV","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct MITA interaction, mechanistic disruption of dimerization and TBK1 recruitment demonstrated; single lab","pmids":["32238587"],"is_preprint":false},{"year":2024,"finding":"TLR2 activation remodels STING signaling by facilitating STING interaction with TRAF6, which suppresses the IRF3-IFN-I response and enhances NF-κB activation, thereby rewiring STING signaling outputs in tumor monocytes.","method":"Co-immunoprecipitation (STING-TRAF6), IRF3 phosphorylation assay, NF-κB reporter, TLR2 agonist treatment, murine tumor models","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating STING-TRAF6 interaction with functional readout of altered signaling; single lab","pmids":["40068600"],"is_preprint":false},{"year":2021,"finding":"The HMGB1-AGER-STING1 pathway mediates sterile inflammation during alkaliptosis: extracellular HMGB1 released by alkaliptotic cancer cells binds to AGER receptor on macrophages and activates the STING1 pathway to produce pro-inflammatory cytokines TNF and IL6. Pharmacological or genetic inhibition of HMGB1, AGER, or STING1 limits cytokine production during alkaliptosis.","method":"Genetic/pharmacological inhibition of HMGB1, AGER, and STING1; cytokine production assays; HMGB1 translocation/release assays","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement by inhibition experiments, but indirect activation of STING1 via AGER; single lab, no direct STING1 binding assay","pmids":["33992959"],"is_preprint":false},{"year":2024,"finding":"Ginkgetin directly binds to the carboxy-terminal domain (CTD) of STING protein, inhibiting STING activation and signal transduction, and alleviates cellular senescence and systemic inflammation in Trex1−/− mice.","method":"Biophysical binding assay (direct binding to STING CTD), STING activation reporter, Trex1−/− mouse inflammation model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biophysical binding to STING CTD domain confirmed, in vivo pharmacodynamic validation; single lab","pmids":["39558862"],"is_preprint":false},{"year":2024,"finding":"Disulfiram (via inhibition of RNF115) impairs STING oligomerization and Golgi localization, reducing STING-mediated inflammation and autoimmune lethality in Trex1−/− mice and STING gain-of-function bone marrow chimeric mice. RNF115 knockout suppresses canonical MITA/STING activation in myeloid cells but not in endothelial cells or fibroblasts, revealing cell-type-specific RNF115-mediated regulation of STING.","method":"RNF115 knockout mouse, disulfiram (DSF) pharmacological treatment, STING oligomerization assay, Golgi localization assay, bone marrow chimera, patient PBMC cytokine measurement","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological epistasis, STING oligomerization/localization mechanistically linked to RNF115, cell-type specificity established; multiple in vivo models","pmids":["38267694"],"is_preprint":false}],"current_model":"STING1 (TMEM173/STING/MITA/MPYS) is an ER-resident transmembrane adaptor that, upon binding of cGAMP (produced by cGAS in response to cytosolic DNA), undergoes conformational closure, C-terminal tail release, and oligomerization/polymerization (via C148 disulfide bonds) to exit the ER—a process requiring TAK1-mediated phosphorylation at S355 for STEEP interaction, followed by translocation to the Golgi where palmitoylation at C88/C91 is essential for full activation; at the Golgi, STING recruits TBK1 (which binds the STING C-terminal tail and phosphorylates S366 through oligomerization-dependent transphosphorylation) and TBK1-phosphorylated IRF3 to induce type I interferons and NF-κB-dependent cytokines; STING activity is terminated by ubiquitination (K48-linked by RNF5 at K150, counteracted by OTUD5 deubiquitinase and ISGylation by HERCs at K150) and autophagic degradation (via WIPI2 direct interaction and UXT/SQSTM1-mediated selective autophagy); beyond innate immune signaling, STING1 also induces noncanonical autophagy activating LRRK2 via GABARAP lipidation, regulates mTORC1 complex formation to restrict lipophagy, interacts with PERK to drive ER stress, drives ZBP1-mediated necroptosis through transcriptional upregulation of ZBP1/MLKL, and has a nuclear function activating AHR for gut homeostasis; gain-of-function mutations in STING1 cause SAVI autoinflammatory disease through constitutive activation, while microtubule interaction restrains lysosomal degradation and NF-κB signaling can amplify STING responses."},"narrative":{"mechanistic_narrative":"STING1 (TMEM173/MITA/MPYS) is an endoplasmic reticulum–resident transmembrane adaptor that couples cytosolic DNA sensing to type I interferon and NF-κB-dependent inflammatory transcription, and whose loss renders cells susceptible to DNA-virus and negative-strand RNA-virus infection [PMID:18724357, PMID:18818105]. In the resting state STING forms an autoinhibited bilayer that tethers two ER membranes via its ligand-binding domain to block ER exit and TBK1 recruitment; binding of the cGAS product 2'3'-cGAMP closes the homodimer, releases the C-terminal tail, and drives a bent filament assembly that deforms the membrane to permit anterograde transport, with disulfide-linked polymerization through Cys148 and disease mutations clustering at the C148 and tail interfaces [PMID:31230712, PMID:37086726]. Productive trafficking requires TAK1-mediated phosphorylation at Ser355, which licenses interaction with STEEP and oligomerization-dependent ER-to-ERGIC translocation, and Golgi palmitoylation at Cys88/Cys91, which is essential for full activation [PMID:37832545, PMID:27324217]; redox state gates this step, since lipid peroxidation under GPX4 loss carbonylates Cys88 and blocks ER-to-Golgi trafficking [PMID:32541831]. At the destination membrane STING recruits TBK1, which docks on the STING C-terminal tail and phosphorylates Ser366 only through oligomerization-dependent transphosphorylation, in turn activating IRF3 [PMID:18818105, PMID:30842653]. STING output is set by a dense post-translational network: K48-linked ubiquitination at Lys150 by RNF5 and proteasomal degradation are opposed by OTUD5 deubiquitination and by HERC5/HERC6 ISGylation at the same Lys150, while RNF115 supplies activating K63-linked ubiquitination, and selective autophagy via UXT/SQSTM1 and direct WIPI2 binding clears STING and cytosolic DNA [PMID:19285439, PMID:32879469, PMID:38652662, PMID:33139700, PMID:35543189, PMID:36872914]; microtubule interaction further restrains trafficking to lysosomal degradation and is lost in gain-of-function mutants [PMID:36857187]. Gain-of-function TMEM173 mutations cause constitutive activation and the autoinflammatory disease SAVI [PMID:25029335], with downstream pathology driven in part by transcriptional upregulation of ZBP1 and MLKL to license RIPK3-dependent necroptosis [PMID:40834903]. Beyond canonical interferon signaling, STING1 also drives PERK-dependent ER stress and reticulophagy [PMID:34338134, PMID:39566842], regulates mTORC1 to restrict lipophagy [PMID:34382907], triggers noncanonical autophagy that activates LRRK2 via GABARAP lipidation [PMID:39982740, PMID:39812709], and acts in the nucleus by binding AHR to control intestinal homeostasis [PMID:38016467].","teleology":[{"year":2008,"claim":"Established STING as the ER-resident adaptor that links cytosolic DNA and virus sensing to IRF3/NF-κB-driven type I interferon, defining its core function in innate immunity.","evidence":"Expression cloning, siRNA loss-of-function, yeast two-hybrid and co-IP, and viral infection in MEFs; independent identification as MITA with TBK1 recruitment and IRF3 activation","pmids":["18724357","18818105"],"confidence":"High","gaps":["Initial reports placed STING at ER, translocon, and mitochondrial outer membrane, leaving the activation-competent compartment unresolved","Ligand and direct sensing mechanism not yet defined"]},{"year":2009,"claim":"Showed STING signaling is actively terminated by ubiquitin-dependent degradation, introducing the concept that STING output is tuned by post-translational turnover.","evidence":"Co-IP, K48-linkage ubiquitination assay and subcellular fractionation identifying RNF5-mediated Lys150 ubiquitination","pmids":["19285439"],"confidence":"High","gaps":["Did not identify opposing deubiquitinase activity","Did not address how Lys150 modification competes with other modifications"]},{"year":2011,"claim":"Demonstrated that common human STING coding variants are hypomorphic, linking specific residues to interferon competence and antibacterial responses.","evidence":"Human cohort SNP analysis, IFN-β reporter with single-SNP mutagenesis, and Listeria infection in primary cells (HAQ haplotype)","pmids":["21248775"],"confidence":"Medium","gaps":["Structural basis for R71H/R293Q loss-of-function not established","Population-level immune consequences not defined"]},{"year":2013,"claim":"Extended STING function in vivo to monocyte-dependent antibacterial defense, showing a chemokine/migration role beyond cell-intrinsic interferon induction.","evidence":"MPYS-deficient mouse Listeria model with adoptive transfer rescue and monocyte migration/chemokine assays","pmids":["23378430"],"confidence":"Medium","gaps":["Molecular link between STING and MCP-1/MCP-3 production not resolved","Cell-intrinsic versus systemic contribution incompletely separated"]},{"year":2014,"claim":"Identified gain-of-function STING mutations as the cause of the autoinflammatory disease SAVI, establishing constitutive STING activation as a human disease mechanism.","evidence":"Candidate gene sequencing, IFNB1 reporter in HEK293T, cGAMP stimulation of patient endothelial cells/fibroblasts, and JAK-inhibitor rescue","pmids":["25029335"],"confidence":"High","gaps":["Structural basis of constitutive activation not yet defined","Downstream effector driving tissue pathology unresolved at this stage"]},{"year":2014,"claim":"Reported a nuclear-envelope-associated chromatin-compaction activity for NET23/STING, raising the possibility of functions outside cytoplasmic signaling.","evidence":"Chromatin compaction screen across cell lines, endogenous-level correlation, Z-VAD controls, and epigenetic mark analysis","pmids":["25386906"],"confidence":"Medium","gaps":["Molecular mechanism of compaction not defined","Relationship to canonical cGAS-STING signaling unclear"]},{"year":2016,"claim":"Defined Golgi palmitoylation at Cys88/Cys91 as an essential activation step, connecting STING trafficking to a lipid modification required for downstream signaling.","evidence":"2-bromopalmitate inhibition, C88/91S mutagenesis, and IFN reporter assays, including disease-mutant STING","pmids":["27324217"],"confidence":"High","gaps":["Palmitoyltransferase responsible not identified here","How palmitoylation enables effector recruitment not structurally resolved"]},{"year":2018,"claim":"Placed STING downstream of mitochondrial quality control, showing that mitophagy restrains STING-driven inflammation by limiting cytosolic mtDNA.","evidence":"Prkn/Pink1/Sting double- and triple-knockout mouse genetic epistasis with behavioral, histological, and cytokine readouts","pmids":["30135585"],"confidence":"High","gaps":["Direct demonstration of mtDNA engaging cGAS-STING in this model not shown","Cell types driving the rescued inflammation not fully resolved"]},{"year":2019,"claim":"Resolved the structural logic of STING activation and TBK1 phosphorylation, explaining why oligomerization is mechanistically required for signaling.","evidence":"Cryo-EM of TBK1–STING and X-ray crystallography of ligand-bound STING with disulfide-crosslinking and mutagenesis (C148 polymerization, S366 trans-phosphorylation)","pmids":["30842653","31230712"],"confidence":"High","gaps":["How polymerization couples to membrane exit not addressed","Partial-antagonist behavior of c-di-GMP not fully resolved in cells"]},{"year":2020,"claim":"Expanded the post-translational control network, showing competing deubiquitination, activating K63-ubiquitination, and redox gating that collectively set STING activation thresholds.","evidence":"OTUD5 K48-deubiquitination and turnover assays with conditional knockout mice; RNF115 K63-ubiquitination and knockout infection models; GPX4-dependent Cys88 carbonylation and trafficking assays","pmids":["32879469","33139700","32541831"],"confidence":"High","gaps":["How these modifications are temporally coordinated on a single STING molecule unresolved","Cell-type specificity of each regulator only partly mapped"]},{"year":2021,"claim":"Linked STING1 to lipid metabolism and to ER-stress/reticulophagy, indicating signaling outputs distinct from the IRF3 interferon program.","evidence":"Co-IP of STING1-mTORC1 with SQSTM1-dependence and lipophagy assays; STING1 polymerization-dependent EIF2AK3/PERK reticulophagy with DDX58 epistasis and translocation-defective mutants","pmids":["34382907","34338134"],"confidence":"Medium","gaps":["Direct STING1 binding partners within mTORC1 not fully mapped","Golgi-independent PERK activation mechanism not structurally defined","Single-lab findings"]},{"year":2023,"claim":"Mechanistically dissected the ER-exit transition and its upstream kinase control, and added an autophagy-coupling interaction and a microtubule-dependent degradative brake.","evidence":"Cryo-EM of autoinhibited bilayer vs active filament; TAK1 in vitro kinase assay mapping S355 and STEEP interaction with trafficking/tumor models; STING-WIPI2 Co-IP with PI3P competition; STING-microtubule Co-IP and trafficking assays with GOF mutants","pmids":["37086726","37832545","36872914","36857187"],"confidence":"High","gaps":["Order of S355 phosphorylation, STEEP binding, and filament formation not fully time-resolved","Whether microtubule and WIPI2 controls act on the same STING pool unclear"]},{"year":2023,"claim":"Identified a DNA-sensing-independent nuclear function in which STING1 binds and activates AHR to regulate gut microbiota and intestinal homeostasis.","evidence":"STING1-AHR Co-IP with domain mapping, nuclear localization, colitis model in STING1-mutant mice, and nuclear-partner proteomics","pmids":["38016467"],"confidence":"Medium","gaps":["How STING1 partitions between nuclear and cytoplasmic pools not defined","Single-lab finding awaiting independent confirmation"]},{"year":2024,"claim":"Refined ISGylation as a Lys150 modification that protects STING from degradation, and showed cell-type-specific RNF115-dependent activation exploitable pharmacologically, plus a STING-PERK axis driving organ fibrosis.","evidence":"HERC5/HERC6 ISGylation at K150 with competing K48-ubiquitination and Herc6 knockout/viral evasion assays; disulfiram/RNF115 knockout oligomerization and Golgi-localization assays in autoimmune models; STING-PERK Co-IP with gain-of-function and conditional-knockout kidney models","pmids":["38652662","38267694","39566842"],"confidence":"High","gaps":["Competition between ISGylation, K48- and K63-ubiquitination at the same residue not kinetically resolved","STING-PERK structural interaction not defined"]},{"year":2025,"claim":"Established STING-driven noncanonical autophagy (CASM) as a route to LRRK2 activation via GABARAP lipidation, and identified ZBP1/MLKL transcriptional upregulation as the necroptotic effector driving SAVI pathology.","evidence":"CASM/GABARAP lipidation and LRRK2 kinase assays with genetic epistasis; Sting1N153S;Ripk3 double-mutant rescue with ZBP1/MLKL expression and complex-formation assays confirmed in human SAVI transcriptomics","pmids":["39982740","39812709","40834903"],"confidence":"High","gaps":["How CASM-LRRK2 signaling integrates with interferon output unclear","Transcriptional machinery linking STING to ZBP1/MLKL induction not mapped"]},{"year":null,"claim":"It remains unresolved how a single STING molecule integrates its competing modifications (S355/S366 phosphorylation, C88/91 palmitoylation, K150 ubiquitination/ISGylation, K63-ubiquitination, carbonylation) and partner interactions to select among interferon, NF-κB, autophagy, PERK/ER-stress, necroptotic, and nuclear AHR outputs in a cell-type-specific manner.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified temporal/structural model reconciling the modification network","Determinants of output selection across cell types undefined","Physiological balance between cytoplasmic signaling and nuclear AHR function unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[21]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,9]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[21,22]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,16,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[20]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8,25,26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,13,17]}],"complexes":["STING-TBK1 signalosome","mTORC1"],"partners":["TBK1","TAK1","WIPI2","RNF5","OTUD5","RNF115","UXT","AHR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86WV6","full_name":"Stimulator of interferon genes protein","aliases":["Endoplasmic reticulum interferon stimulator","ERIS","Mediator of IRF3 activation","hMITA","Transmembrane protein 173"],"length_aa":379,"mass_kda":42.2,"function":"Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta) (PubMed:18724357, PubMed:18818105, PubMed:19433799, PubMed:19776740, PubMed:23027953, PubMed:23747010, PubMed:23910378, PubMed:27801882, PubMed:29973723, PubMed:30842659, PubMed:35045565, PubMed:35388221, PubMed:36808561, PubMed:37832545, PubMed:25704810, PubMed:39255680). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm (PubMed:26300263). Acts by binding cyclic dinucleotides: recognizes and binds cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, cyclic UMP-AMP (2',3'-cUAMP), and cyclic GMP-AMP (cGAMP), a messenger produced by CGAS in response to DNA virus in the cytosol (PubMed:21947006, PubMed:23258412, PubMed:23707065, PubMed:23722158, PubMed:23747010, PubMed:23910378, PubMed:26229117, PubMed:30842659, PubMed:35388221, PubMed:37379839). Upon binding to c-di-GMP, cUAMP or cGAMP, STING1 oligomerizes, translocates from the endoplasmic reticulum and is phosphorylated by TBK1 on the pLxIS motif, leading to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent anti-viral state (PubMed:22394562, PubMed:25636800, PubMed:29973723, PubMed:30842653, PubMed:35045565, PubMed:35388221). Exhibits 2',3' phosphodiester linkage-specific ligand recognition: can bind both 2'-3' linked cGAMP (2'-3'-cGAMP) and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP (PubMed:23747010, PubMed:23910378, PubMed:26300263). The preference for 2'-3'-cGAMP, compared to other linkage isomers is probably due to the ligand itself, whichs adopts an organized free-ligand conformation that resembles the STING1-bound conformation and pays low energy costs in changing into the active conformation (PubMed:26150511). In addition to promote the production of type I interferons, plays a direct role in autophagy (PubMed:30568238, PubMed:30842662). Following cGAMP-binding, STING1 buds from the endoplasmic reticulum into COPII vesicles, which then form the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) (PubMed:30842662). The ERGIC serves as the membrane source for WIPI2 recruitment and LC3 lipidation, leading to formation of autophagosomes that target cytosolic DNA or DNA viruses for degradation by the lysosome (PubMed:30842662). Promotes autophagy by acting as a proton channel that directs proton efflux from the Golgi to facilitate MAP1LC3B/LC3B lipidation (PubMed:37535724). The autophagy- and interferon-inducing activities can be uncoupled and autophagy induction is independent of TBK1 phosphorylation (PubMed:30568238, PubMed:30842662). Autophagy is also triggered upon infection by bacteria: following c-di-GMP-binding, which is produced by live Gram-positive bacteria, promotes reticulophagy (By similarity). May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons (PubMed:18724357). May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II) (By similarity). Involved in intercellular immune signaling. Cross-activated by 2',3'-cGAMP previously generated in virus-infected cells, triggers type I interferon signaling in macrophages and uninfected neighboring cells to propagate and amplify the antiviral immune response (Microbial infection) Antiviral activity is antagonized by oncoproteins, such as papillomavirus (HPV) protein E7 and adenovirus early E1A protein (PubMed:26405230). Such oncoproteins prevent the ability to sense cytosolic DNA (PubMed:26405230)","subcellular_location":"Endoplasmic reticulum membrane; Cytoplasm, perinuclear region; Endoplasmic reticulum-Golgi intermediate compartment membrane; Golgi apparatus membrane; Cytoplasmic vesicle, autophagosome membrane; Mitochondrion outer membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q86WV6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STING1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STING1","total_profiled":1310},"omim":[{"mim_id":"619890","title":"GOLGI-ASSOCIATED RAB2 INTERACTOR 5A; GARIN5A","url":"https://www.omim.org/entry/619890"},{"mim_id":"619535","title":"RING FINGER PROTEIN 115; RNF115","url":"https://www.omim.org/entry/619535"},{"mim_id":"618638","title":"HECT DOMAIN E3 UBIQUITIN PROTEIN LIGASE 3; HECTD3","url":"https://www.omim.org/entry/618638"},{"mim_id":"616086","title":"SprT-LIKE N-TERMINAL DOMAIN PROTEIN; SPRTN","url":"https://www.omim.org/entry/616086"},{"mim_id":"615934","title":"STING-ASSOCIATED VASCULOPATHY, INFANTILE-ONSET; SAVI","url":"https://www.omim.org/entry/615934"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STING1"},"hgnc":{"alias_symbol":["FLJ38577","NET23","ERIS","MPYS","STING","MITA"],"prev_symbol":["TMEM173"]},"alphafold":{"accession":"Q86WV6","domains":[{"cath_id":"-","chopping":"19-139","consensus_level":"high","plddt":86.9143,"start":19,"end":139},{"cath_id":"3.40.50.12100","chopping":"155-317_326-345","consensus_level":"high","plddt":89.5387,"start":155,"end":345}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86WV6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86WV6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86WV6-F1-predicted_aligned_error_v6.png","plddt_mean":83.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STING1","jax_strain_url":"https://www.jax.org/strain/search?query=STING1"},"sequence":{"accession":"Q86WV6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86WV6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86WV6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86WV6"}},"corpus_meta":[{"pmid":"18724357","id":"PMC_18724357","title":"STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18724357","citation_count":2931,"is_preprint":false},{"pmid":"18818105","id":"PMC_18818105","title":"The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation.","date":"2008","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18818105","citation_count":1285,"is_preprint":false},{"pmid":"25029335","id":"PMC_25029335","title":"Activated STING in a vascular and pulmonary syndrome.","date":"2014","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25029335","citation_count":1121,"is_preprint":false},{"pmid":"26603901","id":"PMC_26603901","title":"STING: infection, inflammation and cancer.","date":"2015","source":"Nature reviews. 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Loss of STING rendered murine embryonic fibroblasts susceptible to negative-stranded virus infection and abrogated IFN-β induction by intracellular B-form DNA and herpesviruses. Yeast two-hybrid and co-immunoprecipitation showed STING interacts with RIG-I and with SSR2/TRAPβ (a translocon-associated protein), and RNAi ablation of TRAPβ and SEC61β inhibited STING-mediated IFN-β stimulation.\",\n      \"method\": \"Expression cloning, siRNA knockdown, yeast two-hybrid, co-immunoprecipitation, viral infection assays in MEFs\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — expression cloning with functional loss-of-function, reciprocal co-IP, multiple orthogonal methods; foundational paper replicated across the field\",\n      \"pmids\": [\"18724357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MITA (STING/TMEM173) was identified as a critical mediator linking virus-sensing receptors to IRF3 activation. It localizes to the outer membrane of mitochondria, associates with VISA (mitochondrial adaptor), interacts with IRF3, and recruits kinase TBK1 to the VISA-associated complex. MITA is phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3.\",\n      \"method\": \"Expression cloning, knockdown, co-immunoprecipitation, subcellular fractionation/localization, kinase assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, kinase phosphorylation assay, localization, multiple orthogonal methods; independently identified same gene\",\n      \"pmids\": [\"18818105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The E3 ubiquitin ligase RNF5 interacts with MITA/STING in a viral-infection-dependent manner and targets MITA at Lys150 for K48-linked ubiquitination and proteasomal degradation, thereby negatively regulating virus-triggered IFN signaling. Viral infection causes redistribution of MITA to the ER and RNF5 to mitochondria, and RNF5-mediated ubiquitination and degradation of MITA occurs at the mitochondria.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, ubiquitination assay, viral infection, subcellular fractionation\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific ubiquitination mapped (K150), subcellular localization, multiple orthogonal functional assays in single focused study\",\n      \"pmids\": [\"19285439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Gain-of-function mutations in TMEM173 (STING) cause constitutive activation of the STING pathway, leading to elevated IFN-β transcription and STAT1 phosphorylation, and result in STING-associated vasculopathy with onset in infancy (SAVI). HEK293T cells transfected with mutant STING constructs showed elevated IFNB1 reporter levels. STING is expressed in endothelial cells and cGAMP stimulation caused endothelial activation and apoptosis. JAK inhibitor treatment reduced constitutive STAT1 phosphorylation in patient lymphocytes.\",\n      \"method\": \"Candidate gene sequencing, IFNB1 reporter assay in HEK293T cells, cGAMP stimulation of patient fibroblasts/endothelial cells, phospho-STAT1 assay, JAK inhibitor treatment\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays (reporter, primary cells, patient-derived material, pharmacological rescue) establishing gain-of-function mechanism\",\n      \"pmids\": [\"25029335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Palmitoylation of STING at Cys88/Cys91 at the Golgi is essential for STING activation and induction of type I interferon host defense genes. Palmitoylation inhibitor 2-bromopalmitate (2-BP) suppressed STING palmitoylation and abolished the IFN response. A Cys88/91Ser mutant STING could not induce STING-dependent defense genes. Constitutively active disease-associated STING variants were also inhibited by 2-BP or the Cys88/91Ser mutation.\",\n      \"method\": \"Palmitoylation inhibitor treatment, site-directed mutagenesis (C88/91S), IFN reporter assay, subcellular localization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific mutagenesis combined with pharmacological inhibition and functional readout; mechanism independently validated with disease mutants\",\n      \"pmids\": [\"27324217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM structure of human TBK1 in complex with cGAMP-bound full-length chicken STING revealed that the C-terminal tail of STING adopts a β-strand-like conformation and inserts into a groove between the kinase domain of one TBK1 subunit and the scaffold/dimerization domain of the second TBK1 subunit. The phosphorylation site Ser366 in the STING tail cannot reach the kinase active site of bound TBK1, indicating STING phosphorylation requires oligomerization of both proteins. Mutational analyses validated the TBK1-STING interaction mode.\",\n      \"method\": \"Cryo-EM structural determination, mutational analysis, functional validation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with mutagenesis validation providing atomic-resolution mechanism\",\n      \"pmids\": [\"30842653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Structural and biochemical analyses showed that 2'3'-cGAMP induces closing of the human STING homodimer and release of the C-terminal tail, exposing a polymerization interface leading to disulfide-linked polymer formation via Cys148. Disease-causing hyperactive STING mutations either flank C148 (depending on disulfide formation) or reside in the C-terminal tail binding site (causing constitutive tail release and polymerization). Bacterial cyclic-di-GMP induces an alternative active conformation and acts as a partial antagonist of 2'3'-cGAMP signaling.\",\n      \"method\": \"X-ray crystallography, biochemistry (disulfide crosslinking, polymer formation assays), mutagenesis, ligand competition assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biochemical validation, mutagenesis, and mechanistic dissection of multiple ligand effects\",\n      \"pmids\": [\"31230712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PINK1 and Parkin mitigate STING-dependent inflammation: loss of either PINK1 or Parkin in mice triggered strong inflammatory phenotypes following exhaustive exercise or accumulation of mtDNA mutations, and this inflammation was completely rescued by concurrent loss of STING. The loss of dopaminergic neurons and motor defects in aged Prkn−/−;mutator mice were also rescued by STING loss, indicating that mitophagy restrains innate immunity by limiting STING activation by cytosolic mtDNA.\",\n      \"method\": \"Double-knockout mouse genetic epistasis (Prkn−/−; Pink1−/−; Sting−/−), behavioral testing, histology, cytokine measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo genetic epistasis with multiple phenotypic readouts; replicated across two genetic models (exercise and mutator)\",\n      \"pmids\": [\"30135585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cellular redox homeostasis maintained by GPX4 is required for STING activation. GPX4 deficiency enhanced lipid peroxidation, which led to STING carbonylation at Cys88 and inhibited STING trafficking from the ER to the Golgi complex, thereby specifically attenuating the cGAS-STING pathway and promoting HSV-1 replication in vivo.\",\n      \"method\": \"GPX4 knockout/inhibition, lipid peroxidation assay, STING carbonylation measurement, ER-to-Golgi trafficking assay, in vivo viral infection\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific carbonylation at C88 identified, trafficking phenotype quantified, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"32541831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Apo-STING forms a bilayer with head-to-head and side-by-side packing mediated by its ligand-binding domain (LBD), which holds two ER membranes together to prevent ER exit and eliminate TBK1 recruitment—representing the autoinhibited state. Upon 2'3'-cGAMP binding, STING adopts a bent monolayer filament assembly mediated by both LBD and transmembrane domain (TMD), which deforms the ER membrane to support ER exit and anterograde transport.\",\n      \"method\": \"Cryo-EM structural determination of apo and ligand-bound STING assemblies, biochemical assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures of both autoinhibited and active states providing mechanistic understanding of ER exit\",\n      \"pmids\": [\"37086726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TAK1 kinase is activated by STING in a TAB1-dependent manner prior to STING trafficking and directly phosphorylates STING on Ser355, facilitating interaction of STING with STEEP and promoting STING oligomerization and translocation from the ER to the ERGIC for subsequent activation.\",\n      \"method\": \"Biochemical kinase assay, phosphorylation site identification, co-immunoprecipitation, genetic knockout, STING trafficking assay, in vivo tumor model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with site mapping (S355), Co-IP for STEEP interaction, trafficking phenotype, in vivo validation\",\n      \"pmids\": [\"37832545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STING directly interacts with WIPI2 (key protein for LC3 lipidation in autophagy) to induce autophagosome formation. The STING-WIPI2 interaction is necessary for STING-induced autophagosome formation but does not affect STING activation or intracellular trafficking. The interaction competes with PI3P binding to WIPI2, causing mutual inhibition between STING-induced autophagy and canonical PI3P-dependent autophagy. This interaction enables clearance of cytoplasmic DNA and attenuation of cGAS-STING signaling.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, LC3 lipidation assay, autophagosome formation assay, cytoplasmic DNA clearance assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated by Co-IP, competition with PI3P characterized, functional consequences in multiple assays\",\n      \"pmids\": [\"36872914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NF-κB pathway activation (via TLR, IL-1R, TNFR, GF-R, or PKC signaling) dramatically enhances STING-mediated immune responses by inducing microtubule depolymerization. STING interacts with microtubules, which plays a crucial role in STING intracellular trafficking. NF-κB-induced microtubule depolymerization inhibits STING trafficking to lysosomes for degradation, increasing levels of activated STING. Gain-of-function STING mutations abolish the microtubule-STING interaction causing ligand-independent autoactivation.\",\n      \"method\": \"Co-immunoprecipitation (STING-microtubule), STING trafficking assay, microtubule depolymerization experiments, gain-of-function mutant analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct STING-microtubule interaction demonstrated, trafficking phenotype quantified, mechanistic validation with gain-of-function mutants; multiple methods\",\n      \"pmids\": [\"36857187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The deubiquitinase OTUD5 interacts with STING and cleaves its K48-linked polyubiquitin chains, promoting STING stability. Knockout of OTUD5 resulted in faster STING turnover and impaired type I IFN signaling following cytosolic DNA stimulation. Myeloid-specific Otud5 knockout mice showed increased susceptibility to HSV-1 infection and faster melanoma development.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay (K48 linkage), STING stability/turnover assay, conditional knockout mice, viral infection and tumor models\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — deubiquitination assay with linkage specificity (K48), Co-IP, in vivo knockout phenotype; multiple methods\",\n      \"pmids\": [\"32879469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RNF115 catalyzes K63-linked ubiquitination of MITA/STING after HSV-1 infection; HSV-1-induced aggregation of MITA was impaired in Rnf115−/− cells. This is distinct from its constitutive K48-linked ubiquitination of MAVS in uninfected cells. Rnf115−/− mice exhibit hyper-sensitivity to HSV-1 infection (consistent with reduced MITA activation) and hypo-sensitivity to EMCV infection.\",\n      \"method\": \"Knockout mouse, ubiquitination assay (K63 and K48 linkage), Co-immunoprecipitation, viral infection assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — linkage-specific ubiquitination assay, Co-IP, in vivo knockout with dual viral infection phenotype confirming specificity\",\n      \"pmids\": [\"33139700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STING1 interacts with components of the mTORC1 complex and promotes mTORC1 complex formation under lipotoxic (palmitic acid) conditions in a SQSTM1-dependent manner. STING1 deficiency or rapamycin treatment decreased lipid droplet numbers and restored lipophagy that was inhibited by palmitic acid. Increased mTORC1 activation concomitant with STING1 activation was observed in NAFLD patient liver tissue.\",\n      \"method\": \"Co-immunoprecipitation (STING1-mTORC1 components), STING1 knockout/knockdown, rapamycin treatment, lipid droplet and lipophagy assays, patient tissue analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP demonstrated STING1-mTORC1 interaction, SQSTM1 dependency tested, functional lipophagy phenotype; single lab but multiple methods\",\n      \"pmids\": [\"34382907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UXT (ubiquitously expressed prefoldin-like chaperone) interacts with STING1 upon DNA/cGAMP stimulation and promotes STING1 degradation through selective macroautophagy via SQSTM1. UXT facilitates the interaction between SQSTM1 and STING1 for more efficient autophagic degradation. UXT knockout in mice enhanced cGAS-STING1 signaling during DNA-virus infection and in a lupus model.\",\n      \"method\": \"Co-immunoprecipitation, STING1 degradation assay, autophagy inhibitor experiments, knockout mouse models (viral infection and lupus), patient PBMC analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, mechanistic pathway (SQSTM1-mediated autophagy), in vivo knockout phenotype in two disease models; multiple orthogonal methods\",\n      \"pmids\": [\"35543189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ISGylation of STING at Lys150 by E3 ISGylation ligases HERC5 (human) / HERC6 (mouse) prevents K48-linked ubiquitination and degradation of STING, thereby facilitating STING activation and type I IFN signaling. Herc6 deficiency suppressed HSV-1-induced IFN responses and facilitated viral replication. SARS-CoV-2 papain-like protease cleaves HERC5-mediated ISGylation of STING to suppress host antiviral responses.\",\n      \"method\": \"ISGylation assay (K150 site mapping), K48 ubiquitination assay, Herc6 knockout mice, viral infection assays, viral protease cleavage assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific ISGylation (K150) identified with competing ubiquitination, in vivo knockout phenotype, viral evasion mechanism validated\",\n      \"pmids\": [\"38652662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STING-induced noncanonical autophagy (CASM) activates LRRK2 kinase via lipidation of GABARAP at lysosomes. STING activation generates pH-elevated Golgi-derived vesicles leading to ATG16L1/V-ATPase-dependent noncanonical autophagy, MiT/TFE transcription factor activation (through lipidated GABARAP sequestering FNIP-Folliculin from mTORC1), and ALIX-mediated ESCRT recruitment to mitigate endolysosomal perturbation.\",\n      \"method\": \"STING activation assays, CASM assay, GABARAP lipidation assay, LRRK2 kinase assay, mTORC1 activity measurement, FNIP-Folliculin interaction assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays establishing pathway; single lab, though multiple orthogonal methods\",\n      \"pmids\": [\"39982740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STING activates LRRK2 kinase via the CASM-GABARAP pathway at lysosomes. STING signaling drives GABARAP lipidation, and LRRK2 lysosome recruitment and kinase activation are highly dependent on interactions with GABARAP. Multiple stimuli that perturb lysosomal homeostasis converge on CASM to activate LRRK2.\",\n      \"method\": \"STING activation, LRRK2 kinase assay, GABARAP lipidation assay, lysosome recruitment assay, genetic epistasis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase activation assay with GABARAP dependency and STING genetic epistasis; single lab, multiple methods\",\n      \"pmids\": [\"39812709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STING upregulates ZBP1 and MLKL expression through a transcriptional program, enabling necroptosis via ZBP1-RIPK1-RIPK3 complex formation independently of FADD-RIPK1-RIPK3. In a SAVI mouse model (Sting1N153S), immune-cell-driven pathology and lethality are rescued by Ripk3 co-deletion, establishing STING-driven ZBP1-mediated necroptosis as a central pathogenic mechanism.\",\n      \"method\": \"Genetic epistasis (Sting1N153S/Ripk3 double mutant mice), ZBP1/MLKL expression assay, complex formation assay (Co-IP), caspase-8 conditional deletion model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo genetic rescue (Ripk3 deletion), complex formation identified, confirmed in human SAVI patient transcriptomics and mouse model\",\n      \"pmids\": [\"40834903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STING1 has a nuclear function: its cyclic dinucleotide-binding domain interacts with the N-terminal domain of the transcription factor AHR, activating AHR to control gut microbiota composition and intestinal homeostasis. This nuclear function is independent of DNA sensing and autophagy and shows competitive inhibition with cytoplasmic cGAS-STING1 signaling. AHR ligand protection of colitis was abrogated by mutational inactivation of STING1.\",\n      \"method\": \"Co-immunoprecipitation (STING1-AHR), domain mapping, STING1 nuclear localization assay, STING1 mutant mouse (colitis model), proteomics of nuclear partners\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, in vivo mutant mouse phenotype, proteomics; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38016467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NET23/STING (same protein) strongly promotes chromatin compaction from the nuclear envelope. A correlation between chromatin compaction and endogenous NET23/STING levels was found across multiple human cell lines. STING-induced chromatin compaction is associated with changes in histone methylation and acetylation and is independent of apoptosis (compaction persists with Z-VAD treatment).\",\n      \"method\": \"Chromatin compaction screen (pixel intensity clustering), endogenous level correlation across cell lines, Z-VAD treatment, epigenetic mark analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization/function experiments with multiple cell lines and pharmacological controls; single lab, but multiple methods\",\n      \"pmids\": [\"25386906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A human MPYS/STING haplotype (HAQ: R71H-G230A-R293Q) exhibits >90% loss of ability to stimulate IFN-β production. The loss of IFNβ activity is primarily due to the R71H and R293Q SNPs. Fibroblasts and macrophages expressing HAQ are defective in Listeria monocytogenes infection-induced IFN-β production.\",\n      \"method\": \"Human cohort SNP analysis, IFN-β reporter assay, site-directed mutagenesis (individual SNPs), Listeria infection assay in primary cells\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional loss-of-function mapped to specific residues by mutagenesis, validated in primary cells; single lab\",\n      \"pmids\": [\"21248775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MPYS/STING deficiency leads to increased bacterial burden in the liver upon Listeria monocytogenes infection, correlated with diminished MCP-1/MCP-3 chemokine production and decreased Ly6Chi monocyte frequency in blood and liver. MPYS-deficient Ly6Chi monocytes are intrinsically defective in migration to the liver. Adoptive transfer of wild-type Ly6Chi monocytes into MPYS-deficient mice decreased liver bacterial burden.\",\n      \"method\": \"MPYS-deficient mouse infection model, adoptive transfer, monocyte migration assay, chemokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with multiple phenotypic readouts and adoptive transfer rescue; single lab\",\n      \"pmids\": [\"23378430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STING physically interacts with PERK (the protein kinase RNA-like ER kinase, an arm of ER stress) in kidney tubule cells, and STING agonists induce PERK activation. Mice with a STING activating mutation presented with ER stress and kidney fibroinflammation. Tubule-specific STING deletion protected mice from ER stress and kidney fibrosis.\",\n      \"method\": \"Co-immunoprecipitation (STING-PERK), STING agonist treatment, STING activating-mutation mouse model, conditional tubule-specific STING knockout, kidney fibrosis assays\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct STING-PERK interaction by Co-IP, two mouse genetic models (gain-of-function and conditional KO); single lab\",\n      \"pmids\": [\"39566842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STING1 polymerization is necessary for FMDV (RNA virus)-induced EIF2AK3/PERK-dependent integrated stress response and reticulophagy, independent of STING1 translocation to the Golgi or IFN response activation. Knockdown/knockout of STING1 or EIF2AK3 suppresses FMDV genome replication. FMDV-triggered signaling originates from DDX58/RIG-I which transmits signals to ER-anchored STING1.\",\n      \"method\": \"Knockout/knockdown of STING1 and EIF2AK3, STING1 polymerization assay, reticulophagy assay, viral replication assay, epistasis with DDX58\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (DDX58→STING1→EIF2AK3), polymerization requirement demonstrated, Golgi-independent mechanism confirmed by translocation-defective mutants; single lab\",\n      \"pmids\": [\"34338134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HCMV protein UL42 interacts with MITA/STING and impairs MITA translocation from the ER to perinuclear punctate structures (required for MITA activation) by facilitating p62/LC3B-mediated degradation of TRAPβ. UL42 deficiency enhances HCMV-induced type I IFN production and downstream antiviral gene expression, and impairs viral replication.\",\n      \"method\": \"Co-immunoprecipitation (UL42-MITA), MITA trafficking assay, UL42-deficient HCMV construction, viral replication assay, p62/LC3B-mediated degradation assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct STING interaction, trafficking phenotype, viral genetics; single lab, multiple methods\",\n      \"pmids\": [\"31107917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HCMV protein UL94 interacts with MITA/STING and disrupts MITA dimerization and translocation, and impairs TBK1 recruitment to the MITA signalosome. UL94 deficiency potentiates HCMV-induced type I IFN transcription and downstream antiviral effectors while impairing viral replication.\",\n      \"method\": \"Co-immunoprecipitation (UL94-MITA), MITA dimerization assay, translocation assay, TBK1 recruitment assay, UL94-deficient HCMV\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct MITA interaction, mechanistic disruption of dimerization and TBK1 recruitment demonstrated; single lab\",\n      \"pmids\": [\"32238587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TLR2 activation remodels STING signaling by facilitating STING interaction with TRAF6, which suppresses the IRF3-IFN-I response and enhances NF-κB activation, thereby rewiring STING signaling outputs in tumor monocytes.\",\n      \"method\": \"Co-immunoprecipitation (STING-TRAF6), IRF3 phosphorylation assay, NF-κB reporter, TLR2 agonist treatment, murine tumor models\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating STING-TRAF6 interaction with functional readout of altered signaling; single lab\",\n      \"pmids\": [\"40068600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The HMGB1-AGER-STING1 pathway mediates sterile inflammation during alkaliptosis: extracellular HMGB1 released by alkaliptotic cancer cells binds to AGER receptor on macrophages and activates the STING1 pathway to produce pro-inflammatory cytokines TNF and IL6. Pharmacological or genetic inhibition of HMGB1, AGER, or STING1 limits cytokine production during alkaliptosis.\",\n      \"method\": \"Genetic/pharmacological inhibition of HMGB1, AGER, and STING1; cytokine production assays; HMGB1 translocation/release assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement by inhibition experiments, but indirect activation of STING1 via AGER; single lab, no direct STING1 binding assay\",\n      \"pmids\": [\"33992959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ginkgetin directly binds to the carboxy-terminal domain (CTD) of STING protein, inhibiting STING activation and signal transduction, and alleviates cellular senescence and systemic inflammation in Trex1−/− mice.\",\n      \"method\": \"Biophysical binding assay (direct binding to STING CTD), STING activation reporter, Trex1−/− mouse inflammation model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biophysical binding to STING CTD domain confirmed, in vivo pharmacodynamic validation; single lab\",\n      \"pmids\": [\"39558862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Disulfiram (via inhibition of RNF115) impairs STING oligomerization and Golgi localization, reducing STING-mediated inflammation and autoimmune lethality in Trex1−/− mice and STING gain-of-function bone marrow chimeric mice. RNF115 knockout suppresses canonical MITA/STING activation in myeloid cells but not in endothelial cells or fibroblasts, revealing cell-type-specific RNF115-mediated regulation of STING.\",\n      \"method\": \"RNF115 knockout mouse, disulfiram (DSF) pharmacological treatment, STING oligomerization assay, Golgi localization assay, bone marrow chimera, patient PBMC cytokine measurement\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological epistasis, STING oligomerization/localization mechanistically linked to RNF115, cell-type specificity established; multiple in vivo models\",\n      \"pmids\": [\"38267694\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STING1 (TMEM173/STING/MITA/MPYS) is an ER-resident transmembrane adaptor that, upon binding of cGAMP (produced by cGAS in response to cytosolic DNA), undergoes conformational closure, C-terminal tail release, and oligomerization/polymerization (via C148 disulfide bonds) to exit the ER—a process requiring TAK1-mediated phosphorylation at S355 for STEEP interaction, followed by translocation to the Golgi where palmitoylation at C88/C91 is essential for full activation; at the Golgi, STING recruits TBK1 (which binds the STING C-terminal tail and phosphorylates S366 through oligomerization-dependent transphosphorylation) and TBK1-phosphorylated IRF3 to induce type I interferons and NF-κB-dependent cytokines; STING activity is terminated by ubiquitination (K48-linked by RNF5 at K150, counteracted by OTUD5 deubiquitinase and ISGylation by HERCs at K150) and autophagic degradation (via WIPI2 direct interaction and UXT/SQSTM1-mediated selective autophagy); beyond innate immune signaling, STING1 also induces noncanonical autophagy activating LRRK2 via GABARAP lipidation, regulates mTORC1 complex formation to restrict lipophagy, interacts with PERK to drive ER stress, drives ZBP1-mediated necroptosis through transcriptional upregulation of ZBP1/MLKL, and has a nuclear function activating AHR for gut homeostasis; gain-of-function mutations in STING1 cause SAVI autoinflammatory disease through constitutive activation, while microtubule interaction restrains lysosomal degradation and NF-κB signaling can amplify STING responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STING1 (TMEM173/MITA/MPYS) is an endoplasmic reticulum–resident transmembrane adaptor that couples cytosolic DNA sensing to type I interferon and NF-κB-dependent inflammatory transcription, and whose loss renders cells susceptible to DNA-virus and negative-strand RNA-virus infection [#0, #1]. In the resting state STING forms an autoinhibited bilayer that tethers two ER membranes via its ligand-binding domain to block ER exit and TBK1 recruitment; binding of the cGAS product 2'3'-cGAMP closes the homodimer, releases the C-terminal tail, and drives a bent filament assembly that deforms the membrane to permit anterograde transport, with disulfide-linked polymerization through Cys148 and disease mutations clustering at the C148 and tail interfaces [#6, #9]. Productive trafficking requires TAK1-mediated phosphorylation at Ser355, which licenses interaction with STEEP and oligomerization-dependent ER-to-ERGIC translocation, and Golgi palmitoylation at Cys88/Cys91, which is essential for full activation [#10, #4]; redox state gates this step, since lipid peroxidation under GPX4 loss carbonylates Cys88 and blocks ER-to-Golgi trafficking [#8]. At the destination membrane STING recruits TBK1, which docks on the STING C-terminal tail and phosphorylates Ser366 only through oligomerization-dependent transphosphorylation, in turn activating IRF3 [#1, #5]. STING output is set by a dense post-translational network: K48-linked ubiquitination at Lys150 by RNF5 and proteasomal degradation are opposed by OTUD5 deubiquitination and by HERC5/HERC6 ISGylation at the same Lys150, while RNF115 supplies activating K63-linked ubiquitination, and selective autophagy via UXT/SQSTM1 and direct WIPI2 binding clears STING and cytosolic DNA [#2, #13, #17, #14, #16, #11]; microtubule interaction further restrains trafficking to lysosomal degradation and is lost in gain-of-function mutants [#12]. Gain-of-function TMEM173 mutations cause constitutive activation and the autoinflammatory disease SAVI [#3], with downstream pathology driven in part by transcriptional upregulation of ZBP1 and MLKL to license RIPK3-dependent necroptosis [#20]. Beyond canonical interferon signaling, STING1 also drives PERK-dependent ER stress and reticulophagy [#26, #25], regulates mTORC1 to restrict lipophagy [#15], triggers noncanonical autophagy that activates LRRK2 via GABARAP lipidation [#18, #19], and acts in the nucleus by binding AHR to control intestinal homeostasis [#21].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established STING as the ER-resident adaptor that links cytosolic DNA and virus sensing to IRF3/NF-κB-driven type I interferon, defining its core function in innate immunity.\",\n      \"evidence\": \"Expression cloning, siRNA loss-of-function, yeast two-hybrid and co-IP, and viral infection in MEFs; independent identification as MITA with TBK1 recruitment and IRF3 activation\",\n      \"pmids\": [\"18724357\", \"18818105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Initial reports placed STING at ER, translocon, and mitochondrial outer membrane, leaving the activation-competent compartment unresolved\", \"Ligand and direct sensing mechanism not yet defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed STING signaling is actively terminated by ubiquitin-dependent degradation, introducing the concept that STING output is tuned by post-translational turnover.\",\n      \"evidence\": \"Co-IP, K48-linkage ubiquitination assay and subcellular fractionation identifying RNF5-mediated Lys150 ubiquitination\",\n      \"pmids\": [\"19285439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify opposing deubiquitinase activity\", \"Did not address how Lys150 modification competes with other modifications\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that common human STING coding variants are hypomorphic, linking specific residues to interferon competence and antibacterial responses.\",\n      \"evidence\": \"Human cohort SNP analysis, IFN-β reporter with single-SNP mutagenesis, and Listeria infection in primary cells (HAQ haplotype)\",\n      \"pmids\": [\"21248775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for R71H/R293Q loss-of-function not established\", \"Population-level immune consequences not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended STING function in vivo to monocyte-dependent antibacterial defense, showing a chemokine/migration role beyond cell-intrinsic interferon induction.\",\n      \"evidence\": \"MPYS-deficient mouse Listeria model with adoptive transfer rescue and monocyte migration/chemokine assays\",\n      \"pmids\": [\"23378430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between STING and MCP-1/MCP-3 production not resolved\", \"Cell-intrinsic versus systemic contribution incompletely separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified gain-of-function STING mutations as the cause of the autoinflammatory disease SAVI, establishing constitutive STING activation as a human disease mechanism.\",\n      \"evidence\": \"Candidate gene sequencing, IFNB1 reporter in HEK293T, cGAMP stimulation of patient endothelial cells/fibroblasts, and JAK-inhibitor rescue\",\n      \"pmids\": [\"25029335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of constitutive activation not yet defined\", \"Downstream effector driving tissue pathology unresolved at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reported a nuclear-envelope-associated chromatin-compaction activity for NET23/STING, raising the possibility of functions outside cytoplasmic signaling.\",\n      \"evidence\": \"Chromatin compaction screen across cell lines, endogenous-level correlation, Z-VAD controls, and epigenetic mark analysis\",\n      \"pmids\": [\"25386906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of compaction not defined\", \"Relationship to canonical cGAS-STING signaling unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined Golgi palmitoylation at Cys88/Cys91 as an essential activation step, connecting STING trafficking to a lipid modification required for downstream signaling.\",\n      \"evidence\": \"2-bromopalmitate inhibition, C88/91S mutagenesis, and IFN reporter assays, including disease-mutant STING\",\n      \"pmids\": [\"27324217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyltransferase responsible not identified here\", \"How palmitoylation enables effector recruitment not structurally resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed STING downstream of mitochondrial quality control, showing that mitophagy restrains STING-driven inflammation by limiting cytosolic mtDNA.\",\n      \"evidence\": \"Prkn/Pink1/Sting double- and triple-knockout mouse genetic epistasis with behavioral, histological, and cytokine readouts\",\n      \"pmids\": [\"30135585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of mtDNA engaging cGAS-STING in this model not shown\", \"Cell types driving the rescued inflammation not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the structural logic of STING activation and TBK1 phosphorylation, explaining why oligomerization is mechanistically required for signaling.\",\n      \"evidence\": \"Cryo-EM of TBK1–STING and X-ray crystallography of ligand-bound STING with disulfide-crosslinking and mutagenesis (C148 polymerization, S366 trans-phosphorylation)\",\n      \"pmids\": [\"30842653\", \"31230712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How polymerization couples to membrane exit not addressed\", \"Partial-antagonist behavior of c-di-GMP not fully resolved in cells\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the post-translational control network, showing competing deubiquitination, activating K63-ubiquitination, and redox gating that collectively set STING activation thresholds.\",\n      \"evidence\": \"OTUD5 K48-deubiquitination and turnover assays with conditional knockout mice; RNF115 K63-ubiquitination and knockout infection models; GPX4-dependent Cys88 carbonylation and trafficking assays\",\n      \"pmids\": [\"32879469\", \"33139700\", \"32541831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How these modifications are temporally coordinated on a single STING molecule unresolved\", \"Cell-type specificity of each regulator only partly mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked STING1 to lipid metabolism and to ER-stress/reticulophagy, indicating signaling outputs distinct from the IRF3 interferon program.\",\n      \"evidence\": \"Co-IP of STING1-mTORC1 with SQSTM1-dependence and lipophagy assays; STING1 polymerization-dependent EIF2AK3/PERK reticulophagy with DDX58 epistasis and translocation-defective mutants\",\n      \"pmids\": [\"34382907\", \"34338134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STING1 binding partners within mTORC1 not fully mapped\", \"Golgi-independent PERK activation mechanism not structurally defined\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mechanistically dissected the ER-exit transition and its upstream kinase control, and added an autophagy-coupling interaction and a microtubule-dependent degradative brake.\",\n      \"evidence\": \"Cryo-EM of autoinhibited bilayer vs active filament; TAK1 in vitro kinase assay mapping S355 and STEEP interaction with trafficking/tumor models; STING-WIPI2 Co-IP with PI3P competition; STING-microtubule Co-IP and trafficking assays with GOF mutants\",\n      \"pmids\": [\"37086726\", \"37832545\", \"36872914\", \"36857187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of S355 phosphorylation, STEEP binding, and filament formation not fully time-resolved\", \"Whether microtubule and WIPI2 controls act on the same STING pool unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a DNA-sensing-independent nuclear function in which STING1 binds and activates AHR to regulate gut microbiota and intestinal homeostasis.\",\n      \"evidence\": \"STING1-AHR Co-IP with domain mapping, nuclear localization, colitis model in STING1-mutant mice, and nuclear-partner proteomics\",\n      \"pmids\": [\"38016467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How STING1 partitions between nuclear and cytoplasmic pools not defined\", \"Single-lab finding awaiting independent confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined ISGylation as a Lys150 modification that protects STING from degradation, and showed cell-type-specific RNF115-dependent activation exploitable pharmacologically, plus a STING-PERK axis driving organ fibrosis.\",\n      \"evidence\": \"HERC5/HERC6 ISGylation at K150 with competing K48-ubiquitination and Herc6 knockout/viral evasion assays; disulfiram/RNF115 knockout oligomerization and Golgi-localization assays in autoimmune models; STING-PERK Co-IP with gain-of-function and conditional-knockout kidney models\",\n      \"pmids\": [\"38652662\", \"38267694\", \"39566842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Competition between ISGylation, K48- and K63-ubiquitination at the same residue not kinetically resolved\", \"STING-PERK structural interaction not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established STING-driven noncanonical autophagy (CASM) as a route to LRRK2 activation via GABARAP lipidation, and identified ZBP1/MLKL transcriptional upregulation as the necroptotic effector driving SAVI pathology.\",\n      \"evidence\": \"CASM/GABARAP lipidation and LRRK2 kinase assays with genetic epistasis; Sting1N153S;Ripk3 double-mutant rescue with ZBP1/MLKL expression and complex-formation assays confirmed in human SAVI transcriptomics\",\n      \"pmids\": [\"39982740\", \"39812709\", \"40834903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CASM-LRRK2 signaling integrates with interferon output unclear\", \"Transcriptional machinery linking STING to ZBP1/MLKL induction not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single STING molecule integrates its competing modifications (S355/S366 phosphorylation, C88/91 palmitoylation, K150 ubiquitination/ISGylation, K63-ubiquitination, carbonylation) and partner interactions to select among interferon, NF-κB, autophagy, PERK/ER-stress, necroptotic, and nuclear AHR outputs in a cell-type-specific manner.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified temporal/structural model reconciling the modification network\", \"Determinants of output selection across cell types undefined\", \"Physiological balance between cytoplasmic signaling and nuclear AHR function unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21, 22]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 16, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8, 25, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 13, 17]}\n    ],\n    \"complexes\": [\"STING-TBK1 signalosome\", \"mTORC1\"],\n    \"partners\": [\"TBK1\", \"TAK1\", \"WIPI2\", \"RNF5\", \"OTUD5\", \"RNF115\", \"UXT\", \"AHR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}