Affinage

STING1

Stimulator of interferon genes protein · UniProt Q86WV6

Length
379 aa
Mass
42.2 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2008 High

    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

    PMID:18724357 PMID:18818105

    Open questions at the time
    • 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
  2. 2009 High

    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

    PMID:19285439

    Open questions at the time
    • Did not identify opposing deubiquitinase activity
    • Did not address how Lys150 modification competes with other modifications
  3. 2011 Medium

    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)

    PMID:21248775

    Open questions at the time
    • Structural basis for R71H/R293Q loss-of-function not established
    • Population-level immune consequences not defined
  4. 2013 Medium

    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

    PMID:23378430

    Open questions at the time
    • Molecular link between STING and MCP-1/MCP-3 production not resolved
    • Cell-intrinsic versus systemic contribution incompletely separated
  5. 2014 High

    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

    PMID:25029335

    Open questions at the time
    • Structural basis of constitutive activation not yet defined
    • Downstream effector driving tissue pathology unresolved at this stage
  6. 2014 Medium

    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

    PMID:25386906

    Open questions at the time
    • Molecular mechanism of compaction not defined
    • Relationship to canonical cGAS-STING signaling unclear
  7. 2016 High

    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

    PMID:27324217

    Open questions at the time
    • Palmitoyltransferase responsible not identified here
    • How palmitoylation enables effector recruitment not structurally resolved
  8. 2018 High

    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

    PMID:30135585

    Open questions at the time
    • Direct demonstration of mtDNA engaging cGAS-STING in this model not shown
    • Cell types driving the rescued inflammation not fully resolved
  9. 2019 High

    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)

    PMID:30842653 PMID:31230712

    Open questions at the time
    • How polymerization couples to membrane exit not addressed
    • Partial-antagonist behavior of c-di-GMP not fully resolved in cells
  10. 2020 High

    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

    PMID:32541831 PMID:32879469 PMID:33139700

    Open questions at the time
    • How these modifications are temporally coordinated on a single STING molecule unresolved
    • Cell-type specificity of each regulator only partly mapped
  11. 2021 Medium

    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

    PMID:34338134 PMID:34382907

    Open questions at the time
    • Direct STING1 binding partners within mTORC1 not fully mapped
    • Golgi-independent PERK activation mechanism not structurally defined
    • Single-lab findings
  12. 2023 High

    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

    PMID:36857187 PMID:36872914 PMID:37086726 PMID:37832545

    Open questions at the time
    • 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
  13. 2023 Medium

    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

    PMID:38016467

    Open questions at the time
    • How STING1 partitions between nuclear and cytoplasmic pools not defined
    • Single-lab finding awaiting independent confirmation
  14. 2024 High

    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

    PMID:38267694 PMID:38652662 PMID:39566842

    Open questions at the time
    • Competition between ISGylation, K48- and K63-ubiquitination at the same residue not kinetically resolved
    • STING-PERK structural interaction not defined
  15. 2025 High

    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

    PMID:39812709 PMID:39982740 PMID:40834903

    Open questions at the time
    • How CASM-LRRK2 signaling integrates with interferon output unclear
    • Transcriptional machinery linking STING to ZBP1/MLKL induction not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2 GO:0008289 lipid binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 3 R-HSA-5357801 Programmed Cell Death 1
Partners
AHROTUD5RNF115RNF5TAK1TBK1UXTWIPI2
Complex memberships
STING-TBK1 signalosomemTORC1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 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. Expression cloning, siRNA knockdown, yeast two-hybrid, co-immunoprecipitation, viral infection assays in MEFs Nature High 18724357
2008 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. Expression cloning, knockdown, co-immunoprecipitation, subcellular fractionation/localization, kinase assay Immunity High 18818105
2009 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. Co-immunoprecipitation, overexpression/knockdown, ubiquitination assay, viral infection, subcellular fractionation Immunity High 19285439
2014 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. Candidate gene sequencing, IFNB1 reporter assay in HEK293T cells, cGAMP stimulation of patient fibroblasts/endothelial cells, phospho-STAT1 assay, JAK inhibitor treatment The New England journal of medicine High 25029335
2016 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. Palmitoylation inhibitor treatment, site-directed mutagenesis (C88/91S), IFN reporter assay, subcellular localization Nature communications High 27324217
2019 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. Cryo-EM structural determination, mutational analysis, functional validation Nature High 30842653
2019 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. X-ray crystallography, biochemistry (disulfide crosslinking, polymer formation assays), mutagenesis, ligand competition assays Cell High 31230712
2018 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. Double-knockout mouse genetic epistasis (Prkn−/−; Pink1−/−; Sting−/−), behavioral testing, histology, cytokine measurement Nature High 30135585
2020 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. GPX4 knockout/inhibition, lipid peroxidation assay, STING carbonylation measurement, ER-to-Golgi trafficking assay, in vivo viral infection Nature immunology High 32541831
2023 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. Cryo-EM structural determination of apo and ligand-bound STING assemblies, biochemical assays Molecular cell High 37086726
2023 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. Biochemical kinase assay, phosphorylation site identification, co-immunoprecipitation, genetic knockout, STING trafficking assay, in vivo tumor model Molecular cell High 37832545
2023 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. Co-immunoprecipitation, mutagenesis, LC3 lipidation assay, autophagosome formation assay, cytoplasmic DNA clearance assay The EMBO journal High 36872914
2023 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. Co-immunoprecipitation (STING-microtubule), STING trafficking assay, microtubule depolymerization experiments, gain-of-function mutant analysis Cell reports High 36857187
2020 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. Co-immunoprecipitation, deubiquitination assay (K48 linkage), STING stability/turnover assay, conditional knockout mice, viral infection and tumor models Cellular & molecular immunology High 32879469
2020 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. Knockout mouse, ubiquitination assay (K63 and K48 linkage), Co-immunoprecipitation, viral infection assays Nature communications High 33139700
2021 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. Co-immunoprecipitation (STING1-mTORC1 components), STING1 knockout/knockdown, rapamycin treatment, lipid droplet and lipophagy assays, patient tissue analysis Autophagy Medium 34382907
2022 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. Co-immunoprecipitation, STING1 degradation assay, autophagy inhibitor experiments, knockout mouse models (viral infection and lupus), patient PBMC analysis Autophagy High 35543189
2024 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. ISGylation assay (K150 site mapping), K48 ubiquitination assay, Herc6 knockout mice, viral infection assays, viral protease cleavage assay Cell reports High 38652662
2025 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. STING activation assays, CASM assay, GABARAP lipidation assay, LRRK2 kinase assay, mTORC1 activity measurement, FNIP-Folliculin interaction assay Proceedings of the National Academy of Sciences of the United States of America Medium 39982740
2025 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. STING activation, LRRK2 kinase assay, GABARAP lipidation assay, lysosome recruitment assay, genetic epistasis The Journal of cell biology Medium 39812709
2025 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. Genetic epistasis (Sting1N153S/Ripk3 double mutant mice), ZBP1/MLKL expression assay, complex formation assay (Co-IP), caspase-8 conditional deletion model Nature High 40834903
2023 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. Co-immunoprecipitation (STING1-AHR), domain mapping, STING1 nuclear localization assay, STING1 mutant mouse (colitis model), proteomics of nuclear partners Immunity Medium 38016467
2014 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). Chromatin compaction screen (pixel intensity clustering), endogenous level correlation across cell lines, Z-VAD treatment, epigenetic mark analysis PloS one Medium 25386906
2011 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. Human cohort SNP analysis, IFN-β reporter assay, site-directed mutagenesis (individual SNPs), Listeria infection assay in primary cells Genes and immunity Medium 21248775
2013 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. MPYS-deficient mouse infection model, adoptive transfer, monocyte migration assay, chemokine measurement Journal of immunology Medium 23378430
2024 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. Co-immunoprecipitation (STING-PERK), STING agonist treatment, STING activating-mutation mouse model, conditional tubule-specific STING knockout, kidney fibrosis assays Kidney international Medium 39566842
2021 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. Knockout/knockdown of STING1 and EIF2AK3, STING1 polymerization assay, reticulophagy assay, viral replication assay, epistasis with DDX58 Autophagy Medium 34338134
2019 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. Co-immunoprecipitation (UL42-MITA), MITA trafficking assay, UL42-deficient HCMV construction, viral replication assay, p62/LC3B-mediated degradation assay PLoS pathogens Medium 31107917
2020 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. Co-immunoprecipitation (UL94-MITA), MITA dimerization assay, translocation assay, TBK1 recruitment assay, UL94-deficient HCMV Journal of virology Medium 32238587
2024 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. Co-immunoprecipitation (STING-TRAF6), IRF3 phosphorylation assay, NF-κB reporter, TLR2 agonist treatment, murine tumor models Cancer cell Medium 40068600
2021 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. Genetic/pharmacological inhibition of HMGB1, AGER, and STING1; cytokine production assays; HMGB1 translocation/release assays Biochemical and biophysical research communications Low 33992959
2024 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. Biophysical binding assay (direct binding to STING CTD), STING activation reporter, Trex1−/− mouse inflammation model Advanced science Medium 39558862
2024 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. RNF115 knockout mouse, disulfiram (DSF) pharmacological treatment, STING oligomerization assay, Golgi localization assay, bone marrow chimera, patient PBMC cytokine measurement Cellular & molecular immunology High 38267694

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 2931 18724357
2008 The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 1285 18818105
2014 Activated STING in a vascular and pulmonary syndrome. The New England journal of medicine 1121 25029335
2015 STING: infection, inflammation and cancer. Nature reviews. Immunology 1084 26603901
2018 Parkin and PINK1 mitigate STING-induced inflammation. Nature 1074 30135585
2019 Structural basis of STING binding with and phosphorylation by TBK1. Nature 878 30842653
2018 Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature 713 30405246
2017 A STING-activating nanovaccine for cancer immunotherapy. Nature nanotechnology 656 28436963
2016 Activation of STING requires palmitoylation at the Golgi. Nature communications 586 27324217
2022 The cGAS-STING pathway and cancer. Nature cancer 522 36510011
2020 cGAS-STING, an important pathway in cancer immunotherapy. Journal of hematology & oncology 498 32571374
2009 The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. Immunity 407 19285439
2016 The cGAS-STING Defense Pathway and Its Counteraction by Viruses. Cell host & microbe 355 26867174
2020 Redox homeostasis maintained by GPX4 facilitates STING activation. Nature immunology 351 32541831
2019 STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition. Cell 345 31230712
2021 STING Agonists as Cancer Therapeutics. Cancers 333 34070756
2020 STING cyclic dinucleotide sensing originated in bacteria. Nature 315 32877915
2019 STING pathway agonism as a cancer therapeutic. Immunological reviews 281 31355488
2020 Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and Aging. Trends in neurosciences 255 33187730
2020 Trial watch: STING agonists in cancer therapy. Oncoimmunology 229 32934881
2017 Evolutionary Origins of cGAS-STING Signaling. Trends in immunology 227 28416447
2021 The STING1 network regulates autophagy and cell death. Signal transduction and targeted therapy 214 34078874
2019 STING activation in cancer immunotherapy. Theranostics 192 31695799
2020 The interactions between cGAS-STING pathway and pathogens. Signal transduction and targeted therapy 183 32532954
2023 NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking. Cell reports 164 36857187
2013 The cGAS-STING pathway for DNA sensing. Molecular cell 144 23870141
2018 SnapShot: CGAS-STING Signaling. Cell 133 29570996
2020 STING Pathway Expression Identifies NSCLC With an Immune-Responsive Phenotype. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 132 32068166
2022 Targeting STING to promote antitumor immunity. Trends in cell biology 130 35931610
2024 The balance of STING signaling orchestrates immunity in cancer. Nature immunology 116 38918609
2011 Identification and characterization of a loss-of-function human MPYS variant. Genes and immunity 102 21248775
2021 The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation. British journal of pharmacology 94 34460100
2021 Lipotoxicity-induced STING1 activation stimulates MTORC1 and restricts hepatic lipophagy. Autophagy 93 34382907
2020 OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING. Cellular & molecular immunology 86 32879469
2019 STING palmitoylation as a therapeutic target. Cellular & molecular immunology 83 30796349
2025 Regulation of the cGAS-STING Pathway. Annual review of immunology 80 40085836
2024 Mitophagy and cGAS-STING crosstalk in neuroinflammation. Acta pharmaceutica Sinica. B 80 39220869
2014 MITA/STING: a central and multifaceted mediator in innate immune response. Cytokine & growth factor reviews 80 24929887
2019 A STING to inflammation and autoimmunity. Journal of leukocyte biology 79 30990921
2020 RNF115 plays dual roles in innate antiviral responses by catalyzing distinct ubiquitination of MAVS and MITA. Nature communications 78 33139700
2022 cGAS-STING signaling. Current biology : CB 76 35820380
2021 STING Operation at the ER/Golgi Interface. Frontiers in immunology 76 34012437
2017 Regulating STING in health and disease. Journal of inflammation (London, England) 76 28596706
2022 Activation of Stimulator of IFN Genes (STING) Causes Proteinuria and Contributes to Glomerular Diseases. Journal of the American Society of Nephrology : JASN 69 36198430
2023 The mechanism of STING autoinhibition and activation. Molecular cell 68 37086726
2025 Targeting tumor monocyte-intrinsic PD-L1 by rewiring STING signaling and enhancing STING agonist therapy. Cancer cell 61 40068600
2019 Neuroinflammation and the cGAS-STING pathway. Journal of neurophysiology 61 30673358
2023 STING directly recruits WIPI2 for autophagosome formation during STING-induced autophagy. The EMBO journal 60 36872914
2022 Nanodelivery of cGAS-STING activators for tumor immunotherapy. Trends in pharmacological sciences 58 36089410
2019 Human cytomegalovirus protein UL42 antagonizes cGAS/MITA-mediated innate antiviral response. PLoS pathogens 57 31107917
2023 Regulation of cGAS and STING signaling during inflammation and infection. The Journal of biological chemistry 55 37247757
2013 STING/MPYS mediates host defense against Listeria monocytogenes infection by regulating Ly6C(hi) monocyte migration. Journal of immunology (Baltimore, Md. : 1950) 52 23378430
2024 Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma. The Journal of clinical investigation 50 38226619
2023 Nanoparticle-Mediated STING Activation for Cancer Immunotherapy. Advanced healthcare materials 50 36905358
2023 SARS-CoV-2 nonstructural protein 6 triggers endoplasmic reticulum stress-induced autophagy to degrade STING1. Autophagy 47 37482689
2022 UXT attenuates the CGAS-STING1 signaling by targeting STING1 for autophagic degradation. Autophagy 46 35543189
2021 STING Signaling and Sterile Inflammation. Frontiers in immunology 46 34659260
2020 Molecular and spatial mechanisms governing STING signalling. The FEBS journal 46 33237620
2014 Adding to the STING. Immunity 46 25526298
2023 TAK1 is an essential kinase for STING trafficking. Molecular cell 45 37832545
2025 STING-induced noncanonical autophagy regulates endolysosomal homeostasis. Proceedings of the National Academy of Sciences of the United States of America 44 39982740
2020 Structural Insights into STING Signaling. Trends in cell biology 43 32302551
2023 Targeting STING in cancer: Challenges and emerging opportunities. Biochimica et biophysica acta. Reviews on cancer 42 37717857
2019 Bioactive modulators targeting STING adaptor in cGAS-STING pathway. Drug discovery today 42 31758915
2024 Ginkgetin Alleviates Inflammation and Senescence by Targeting STING. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 41 39558862
2022 Activation of STING Based on Its Structural Features. Frontiers in immunology 41 35928815
2025 A STING-CASM-GABARAP pathway activates LRRK2 at lysosomes. The Journal of cell biology 40 39812709
2025 MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction. Molecular cell 40 40614706
2023 Nuclear localization of STING1 competes with canonical signaling to activate AHR for commensal and intestinal homeostasis. Immunity 40 38016467
2021 STING and liver disease. Journal of gastroenterology 40 34159442
2020 cGAS/STING: novel perspectives of the classic pathway. Molecular biomedicine 40 35006429
2019 STING modulators: Predictive significance in drug discovery. European journal of medicinal chemistry 40 31419779
2022 Regulation and function of the cGAS-MITA/STING axis in health and disease. Cell insight 39 37192983
2020 Human Cytomegalovirus Protein UL94 Targets MITA to Evade the Antiviral Immune Response. Journal of virology 39 32238587
2011 STING-dependent signaling. Nature immunology 38 21934672
2023 Huangkui capsule attenuates diabetic kidney disease through the induction of mitophagy mediated by STING1/PINK1 signaling in tubular cells. Phytomedicine : international journal of phytotherapy and phytopharmacology 35 37517171
2024 ER: a critical hub for STING signaling regulation. Trends in cell biology 34 38423853
2023 Stimulator of interferon genes (STING): Key therapeutic targets in ischemia/reperfusion injury. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 32 37699319
2023 Potential Therapeutic Value of the STING Inhibitors. Molecules (Basel, Switzerland) 31 37049889
2021 The HMGB1-AGER-STING1 pathway mediates the sterile inflammatory response to alkaliptosis. Biochemical and biophysical research communications 29 33992959
2021 STING1 is essential for an RNA-virus triggered autophagy. Autophagy 29 34338134
2024 The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis. Kidney international 28 39566842
2021 STING1 in sepsis: Mechanisms, functions, and implications. Chinese journal of traumatology = Zhonghua chuang shang za zhi 28 34334261
2024 ISGylation by HERCs facilitates STING activation. Cell reports 27 38652662
2020 When STING Meets Viruses: Sensing, Trafficking and Response. Frontiers in immunology 27 33133062
2022 Emerging dimensions of cellular cGAS-STING signaling. Current opinion in immunology 26 35124516
2018 Delicate regulation of the cGAS-MITA-mediated innate immune response. Cellular & molecular immunology 26 29456253
2024 Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115. Cellular & molecular immunology 25 38267694
2023 Targeting STING: From antiviral immunity to treat osteoporosis. Frontiers in immunology 25 36741390
2023 SPOP Mutations Target STING1 Signaling in Prostate Cancer and Create Therapeutic Vulnerabilities to PARP Inhibitor-Induced Growth Suppression. Clinical cancer research : an official journal of the American Association for Cancer Research 25 37581614
2020 Balancing STING in antimicrobial defense and autoinflammation. Cytokine & growth factor reviews 24 32563552
2020 STING or Sting: cGAS-STING-Mediated Immune Response to Protozoan Parasites. Trends in parasitology 23 32736985
2014 NET23/STING promotes chromatin compaction from the nuclear envelope. PloS one 23 25386906
2025 STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD. Nature 22 40834903
2018 On taking the STING out of immune activation. Journal of leukocyte biology 22 29431896
2017 MITA/STING and Its Alternative Splicing Isoform MRP Restrict Hepatitis B Virus Replication. PloS one 22 28056087
2023 STING signaling in inflammaging: a new target against musculoskeletal diseases. Frontiers in immunology 21 37492580
2022 Activating STING1-dependent immune signaling in TP53 mutant and wild-type acute myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America 21 35759659
2022 Zebrafish MARCH8 downregulates fish IFN response by targeting MITA and TBK1 for protein degradation. Developmental and comparative immunology 21 35764162
2024 Selenium Attenuates Radiation Colitis by Regulating cGAS-STING Signaling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20 39348242

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