Affinage

CGAS

Cyclic GMP-AMP synthase · UniProt Q8N884

Length
522 aa
Mass
58.8 kDa
Annotated
2026-06-09
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

cGAS is a cytosolic and nuclear nucleic-acid sensor that initiates innate immune and cell-fate responses by detecting aberrant DNA and synthesizing the second messenger 2'3'-cGAMP, which activates downstream STING signaling (PMID:23722159). A DNA-induced structural switch converts cGAS into an active nucleotidyl transferase that forms cGAMP, and beyond B-form dsDNA it also recognizes cytosolic RNA:DNA hybrids (PMID:23722159, PMID:25425575). Activation requires assembly of a 2:2 cGAS-dsDNA complex, and cGAS is held inactive when bound to the nucleosome acidic patch via two conserved arginines that occlude its dsDNA-binding surface and lock it as a monomer (PMID:32911482, PMID:32913000). This sets up cGAS as a sensor of genome instability: it accumulates at micronuclei following nuclear envelope rupture and is activated by exposed chromatin in a cell-cycle-dependent manner to drive interferon-stimulated gene expression, cellular senescence, and the senescence-associated secretory phenotype (PMID:28738408, PMID:28533362). During mitosis, when cGAS contacts chromatin, it is restrained by nucleosome competition, Aurora kinase B-mediated N-terminal hyperphosphorylation, and blockade of oligomerization, while in arrested cells cGAS-dependent IRF3 phosphorylation can instead promote apoptosis (PMID:31299200, PMID:33542149). cGAS activity is set by an extensive layer of regulators and modifications: G3BP1 promotes large activating cGAS complexes and DNA binding, MRE11-RAD50-NBN displaces cGAS from nucleosome sequestration to enable activation by oncogenic stress and ionizing radiation, and ZBP1 nucleates a cGAS-RIPK1-RIPK3 complex to sense mitochondrial genome instability (PMID:30510222, PMID:38200309, PMID:37352855). Inhibitory modifications include DNA-PK phosphorylation, ZDHHC18-mediated C474 palmitoylation, PRMT1-mediated Arg133 methylation, PARP1-mediated PARylation at Asp191, and AARS2-mediated lactylation, while HERC5-mediated ISGylation enhances oligomerization and activity (PMID:33273464, PMID:35438208, PMID:37193698, PMID:35460603, PMID:39322678, PMID:38421872). Nuclear cGAS is degraded by the CRL5-SPSB3 ubiquitin ligase via a C-terminal NN degron, and in the nucleus cGAS suppresses homologous recombination by interacting with PARP1 through poly(ADP-ribose) to impede the PARP1-Timeless complex (PMID:38418882, PMID:30356214). cGAS also acts as a selective autophagy receptor for micronuclei through an LC3B-interacting region, and its DNA sensing is tuned by RNA-promoted phase separation (PMID:33752561, PMID:36382803). The activated pathway has broad physiological consequences, including STING-dependent autophagy, antitumor immunity through cGAMP transfer to myeloid cells, and age-associated microglial dysfunction and neurodegeneration (PMID:30842662, PMID:31665636, PMID:37532932).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2013 High

    Established the catalytic logic of cGAS by showing how DNA binding licenses cGAMP synthesis, answering how a cytosolic sensor converts DNA detection into a diffusible second messenger.

    Evidence X-ray crystallography of cGAS alone and with DNA/ATP/GTP plus in vitro enzymatic assays

    PMID:23722159

    Open questions at the time
    • Did not address how cGAS distinguishes self from non-self DNA in cells
    • Did not resolve higher-order oligomeric active states
  2. 2014 High

    Extended cGAS ligand specificity beyond dsDNA to RNA:DNA hybrids, broadening the range of nucleic acids that trigger the pathway.

    Evidence In vitro cGAMP synthesis with recombinant cGAS and THP-1 knockout cells challenged with synthetic RNA:DNA hybrids

    PMID:25425575

    Open questions at the time
    • Relative physiological contribution of hybrid sensing versus dsDNA unresolved
    • Did not define structural basis of hybrid recognition
  3. 2017 High

    Linked cGAS to genome instability and aging-related programs by showing it senses micronuclear chromatin and drives senescence and SASP, recasting it as a sensor of cell-intrinsic damage.

    Evidence Live-cell imaging and micronuclei analysis (28738408); cGAS knockout MEFs with DNA-damage challenge and fractionation (28533362)

    PMID:28533362 PMID:28738408

    Open questions at the time
    • Did not explain how cGAS avoids constitutive activation by genomic chromatin
    • Did not define the structural inhibitory mechanism
  4. 2018 High

    Revealed nuclear, signaling-independent functions of cGAS, showing it suppresses homologous recombination and identifying spatial control of its localization.

    Evidence Co-IP, importin-α assays, Y215 mutagenesis, and HR repair assays in mouse and human models

    PMID:30356214

    Open questions at the time
    • Mechanism coupling PAR-binding to Timeless displacement incompletely defined
    • Interplay with cGAS cytosolic immune role unclear
  5. 2018 High

    Identified G3BP1 as a positive cofactor that promotes activating cGAS complexes, addressing how cGAS achieves efficient DNA binding.

    Evidence Reciprocal Co-IP, DNA binding assays, G3BP1 loss-of-function, and in vivo autoinflammation model

    PMID:30510222

    Open questions at the time
    • Structural basis of G3BP1-cGAS complex not resolved
    • Did not establish whether G3BP1 acts within condensates
  6. 2019 High

    Resolved the nucleosome paradox and a non-canonical apoptotic output, showing nucleosomes competitively block cGAS while mitotic-arrest cGAS-IRF3 signaling can trigger apoptosis.

    Evidence In vitro nucleosome competition assays, Taxol-induced mitotic arrest, IRF3 phosphorylation and apoptosis readouts, xenografts

    PMID:31299200

    Open questions at the time
    • Molecular geometry of nucleosome inhibition not yet structurally defined here
    • Transcription-independent IRF3-Bcl-xL link mechanistically incomplete
  7. 2019 High

    Defined a TBK1- and interferon-independent autophagy branch downstream of cGAS-cGAMP-STING, expanding pathway outputs beyond transcription.

    Evidence Genetic epistasis (TBK1, WIPI2, ATG5), LC3 lipidation and fractionation assays, ancestral STING

    PMID:30842662

    Open questions at the time
    • This step centers on STING rather than cGAS-intrinsic mechanism
    • Quantitative contribution of autophagy to host defense not resolved
  8. 2020 High

    Provided the structural mechanism of cGAS autoinhibition, showing nucleosome acidic-patch binding locks cGAS as an inactive monomer by occluding its dsDNA surface.

    Evidence Two independent cryo-EM structures of cGAS-nucleosome complexes with interface mutagenesis and cell-based activity assays

    PMID:32911482 PMID:32913000

    Open questions at the time
    • Did not establish how cGAS is released from nucleosomes for activation
    • Dynamics of monomer-to-oligomer transition in cells unresolved
  9. 2020 Medium

    Began defining post-translational suppression of cGAS, identifying DNA-PK phosphorylation as a brake on enzymatic activity, and demonstrated cell-extrinsic antitumor signaling via cGAMP transfer.

    Evidence Kinase assays with DNA-PKcs KO cells (33273464); gap-junction blockade and cell-specific cGAS/STING KO tumor models (31665636)

    PMID:31665636 PMID:33273464

    Open questions at the time
    • Phosphosite mapping and stoichiometry incompletely defined
    • Mechanism of cGAMP intercellular transfer not fully characterized
  10. 2021 High

    Detailed how cGAS is silenced during mitosis and how micronuclear cGAS is restrained, explaining avoidance of autoimmune activation when cGAS encounters chromatin.

    Evidence Mitotic kinase/Aurora B phosphorylation and oligomerization assays (33542149); TREX1 ER-tethering and micronuclei degradation assays (33476576)

    PMID:33476576 PMID:33542149

    Open questions at the time
    • Identity of all mitotic kinase sites incomplete
    • How ER access to micronuclei is timed not fully resolved
  11. 2021 Medium

    Established cGAS as a selective autophagy receptor for micronuclei, linking it to its own negative feedback through LC3B-mediated clearance.

    Evidence Co-IP with LC3B, LIR mutagenesis, autophagy flux and micronuclei quantification under genotoxic stress

    PMID:33752561

    Open questions at the time
    • Single-lab Co-IP plus LIR mutagenesis without independent confirmation
    • Relationship to cGAS catalytic activity during micronucleophagy unclear
  12. 2022 Medium

    Expanded the inhibitory PTM landscape, defining palmitoylation, methylation, PARylation, and RNA-driven phase separation as distinct tuning mechanisms of cGAS DNA binding, dimerization, and condensate formation.

    Evidence Writer-enzyme assays and residue mutagenesis for ZDHHC18/C474, PRMT1/R133, PARP1/D191; in vitro phase separation and RNA co-IP

    PMID:35438208 PMID:35460603 PMID:36382803 PMID:37193698

    Open questions at the time
    • Crosstalk and hierarchy among these PTMs not established
    • Physiological triggers governing each modification incompletely defined
  13. 2023 High

    Uncovered organelle-localized and complex-based functions, placing cGAS at mitochondria with DRP1 and within a ZBP1-RIPK1-RIPK3 module sensing mitochondrial genome instability, with aging consequences in microglia.

    Evidence Fractionation/imaging and Co-IP (DRP1, ZBP1) with KO mice and ferroptosis/STAT1 readouts; cGAS gain-of-function microglia with snRNA-seq and behavior

    PMID:36864172 PMID:37352855 PMID:37532932

    Open questions at the time
    • Whether mitochondrial cGAS retains catalytic activity at that site unclear
    • Distinct contributions of cGAS within the ZBP1 complex versus canonical sensing unresolved
  14. 2024 High

    Resolved how cGAS is mobilized for activation and degraded when nuclear, identifying MRN-mediated nucleosome displacement, CRL5-SPSB3-mediated nuclear degradation, lactylation, and ISGylation as switches controlling activity.

    Evidence Co-IP and nucleosome displacement assays (MRE11), cryo-EM and degron mutagenesis (SPSB3/NN), in vitro lactylation with knock-in mice (AARS2), ISGylation residue mapping (HERC5)

    PMID:38200309 PMID:38418882 PMID:38421872 PMID:39322678

    Open questions at the time
    • How these opposing modifications are integrated in time and space unresolved
    • Quantitative balance between MRN-driven activation and SPSB3-driven degradation undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many activating and inhibitory inputs (nucleosome sequestration, MRN displacement, multiple PTMs, phase separation, organelle localization, and degradation) are integrated into a single quantitative threshold governing when and where cGAS fires remains unresolved.
  • No unified model of competing regulatory inputs
  • Spatiotemporal coordination of nuclear, cytosolic, and mitochondrial pools undefined
  • Relative weight of catalytic versus non-catalytic (HR, autophagy) functions in vivo unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0003723 RNA binding 2 GO:0016740 transferase activity 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0140299 molecular sensor activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3 GO:0005739 mitochondrion 2 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 2 R-HSA-73894 DNA Repair 1
Partners
DRP1G3BP1MAP1LC3BMRE11PARP1SPSB3STING1ZBP1
Complex memberships
CRL5-SPSB3 ubiquitin ligase (substrate)ZBP1-cGAS-RIPK1-RIPK3 complexcGAS-PARP1 (poly(ADP-ribose)-mediated)

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Crystal structure of cGAS alone and in complex with DNA, ATP, and GTP revealed that cGAS catalyzes dinucleotide (cGAMP) formation via a DNA-induced structural switch; cGAS possesses structural similarity to OAS1 and contains a unique zinc thumb that recognizes B-form dsDNA. X-ray crystallography, in vitro enzymatic assays, active-site structural analysis Nature High 23722159
2014 cGAS recognizes cytosolic RNA:DNA hybrids in addition to dsDNA; recombinant cGAS produced cGAMP upon RNA:DNA hybrid recognition in vitro, and THP-1 knockout cells confirmed this response is mediated entirely through the cGAS-STING pathway. In vitro cGAMP synthesis assay with recombinant cGAS, THP-1 knockout cell lines, cytosolic delivery of synthetic RNA:DNA hybrids The EMBO journal High 25425575
2017 cGAS localizes to micronuclei arising from genome instability; breakdown of the micronuclear envelope leads to rapid cGAS accumulation at chromatin, and cGAS is activated by chromatin in a cell-cycle-dependent manner, triggering interferon-stimulated gene expression in micronucleated cells. Live-cell imaging, laser microdissection, single-cell transcriptomics, mouse model of autoinflammation, human cancer cell lines Nature High 28738408
2017 cGAS is essential for cellular senescence and the senescence-associated secretory phenotype (SASP); deletion of cGAS accelerated immortalization of MEFs and abrogated SASP induced by DNA-damaging agents. cGAS localizes in the cytoplasm of non-dividing cells but enters the nucleus and associates with chromatin DNA during mitosis. cGAS knockout/deletion in MEFs, radiation and etoposide treatment, subcellular fractionation, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 28533362
2018 Nuclear cGAS suppresses homologous recombination (HR) DNA repair. DNA damage induces nuclear translocation of cGAS dependent on importin-α; phosphorylation of cGAS at Tyr215 by B-lymphoid tyrosine kinase (BLK) facilitates cytosolic retention. In the nucleus, cGAS is recruited to DSBs, interacts with PARP1 via poly(ADP-ribose), and the cGAS-PARP1 interaction impedes formation of the PARP1-Timeless complex, suppressing HR. Co-immunoprecipitation, nuclear fractionation, importin-α interaction assays, site-directed mutagenesis (Y215), HR repair assays, mouse and human models Nature High 30356214
2018 G3BP1 physically interacts with cGAS and promotes formation of large cGAS complexes, enhancing DNA binding of cGAS and its activation; G3BP1 deficiency leads to inefficient DNA binding by cGAS and inhibited cGAS-dependent IFN production. Co-immunoprecipitation, DNA binding assays, G3BP1 knockdown/knockout, in vivo mouse autoinflammation model Nature immunology High 30510222
2019 cGAS-dependent IRF3 phosphorylation during mitotic arrest promotes apoptosis through transcription-independent alleviation of Bcl-xL-dependent suppression of mitochondrial outer membrane permeabilization; nucleosomes competitively inhibit DNA-dependent cGAS activation so cGAS-STING is not effectively activated during normal mitosis. In vitro cGAS activation assays with nucleosomes, mitotic arrest assays (Taxol), IRF3 phosphorylation measurement, apoptosis assays, cGAS/IRF3 expression in xenograft tumors Cell High 31299200
2019 STING activates autophagy through a TBK1- and interferon-independent mechanism upon cGAMP binding; STING translocates to the ERGIC and Golgi in a COP-II- and ARF GTPase-dependent manner, and STING-containing ERGIC serves as a membrane source for LC3 lipidation (autophagosome biogenesis) dependent on WIPI2 and ATG5. Genetic knockouts (TBK1, WIPI2, ATG5, ULK, VPS34-beclin), LC3 lipidation assays, subcellular fractionation, cGAMP stimulation, use of ancestral STING from Nematostella vectensis Nature High 30842662
2020 Cryo-EM structure of human cGAS bound to nucleosomes revealed that cGAS makes extensive contacts with the acidic patch of H2A-H2B and nucleosomal DNA; nucleosome binding locks cGAS into an inactive monomeric state through steric hindrance. Mutations to the cGAS-acidic patch interface abolished nucleosome-mediated inhibition in vitro and unleashed cGAS activity on genomic DNA in living cells. Cryo-electron microscopy structure determination, biochemical binding assays, mutagenesis of cGAS-acidic patch interface, cell-based activity assays Nature High 32911482
2020 Cryo-EM structure (3.3 Å) of cGAS bound to nucleosome core particle showed cGAS uses two conserved arginines to anchor to the nucleosome acidic patch; this nucleosome-binding interface exclusively occupies the strong dsDNA-binding surface on cGAS and sterically prevents cGAS from oligomerizing into the active 2:2 cGAS-dsDNA state. Cryo-electron microscopy, biochemical assays, structural analysis of cGAS-nucleosome interface Science High 32913000
2020 DNA-PK (DNA-PKcs) phosphorylates cGAS and suppresses its enzymatic activity; DNA-PK deficiency reduces cGAS phosphorylation and promotes antiviral innate immune responses. Kinase assay (DNA-PK phosphorylation of cGAS), DNA-PKcs knockout/missense mutant cells, antiviral IFN response measurement Nature communications Medium 33273464
2021 cGAS activity is selectively suppressed during mitosis by two parallel mechanisms: (1) hyperphosphorylation of the N-terminus by mitotic kinases including Aurora kinase B, which blocks chromatin sensing; and (2) prevention of oligomerization of chromatin-bound cGAS. Together these prevent autoimmune activation when cGAS contacts chromatin during mitosis. Biochemical phosphorylation assays, Aurora kinase B inhibition/knockdown, mitotic cell fractionation, cGAS activity assays in synchronized human cell lines Science High 33542149
2021 TREX1 (ER-associated nuclease) inhibits cGAS activation at micronuclei by degrading micronuclear DNA upon micronuclear envelope rupture; the ER accesses ruptured micronuclei and enables TREX1 nucleolytic attack. TREX1 mutations that untether it from the ER disrupt localization to micronuclei and enhance cGAS activation. Micronuclei purification, TREX1 localization assays, ER access imaging, TREX1 mutant cell analysis, cGAS activation measurement Molecular cell High 33476576
2021 cGAS functions as a micronucleophagy receptor: it accumulates in autophagic machinery and directly interacts with MAP1LC3B via a MAP1LC3-interacting region (LIR). This interaction is essential for LC3 recruitment to micronuclei and their clearance via selective autophagy, which dampens cGAMP production induced by genotoxic stress. Co-immunoprecipitation of cGAS with LC3B, LIR motif mutagenesis, autophagy flux assays, micronuclei quantification, genotoxic stress experiments Autophagy Medium 33752561
2022 Palmitoylation of cGAS at C474, catalyzed mainly by the palmitoyltransferase ZDHHC18, restricts cGAS enzymatic activity by reducing the interaction between cGAS and dsDNA and inhibiting cGAS dimerization; dsDNA promotes this palmitoylation modification. Palmitoylation assays, ZDHHC18 knockout in human and mouse cells, site-directed mutagenesis (C474), DNA binding assays, dimerization assays, Zdhhc18-deficient mouse model The EMBO journal High 35438208
2022 PRMT1 methylates cGAS at conserved Arg133, preventing cGAS dimerization and suppressing cGAS/STING signaling in cancer cells; PRMT1 ablation activates cGAS/STING-dependent DNA sensing and elevates type I and II interferon response genes. In vitro methylation assay, site-directed mutagenesis (R133), cGAS dimerization assay, PRMT1 KO/inhibition in cells, in vivo mouse tumor model Nature communications Medium 37193698
2022 Cytoplasmic PARP1 (translocated via DNA-PK-mediated Thr594 phosphorylation) directly PARylates cGAS at Asp191, inhibiting its DNA-binding ability and antiviral immunity. Co-immunoprecipitation, in vitro PARylation assay, site-directed mutagenesis (D191), cytoplasmic fractionation, antiviral assays in vitro and in vivo Molecular cell High 35460603
2022 Cytoplasmic RNAs promote phase separation of cGAS in vitro and colocalize with phase-separated cGAS-dsDNA condensates in cells; RNAs enhance cGAS enzymatic activity when dsDNA concentration is low by promoting condensate formation. In vitro phase separation assays, cGAS-RNA co-immunoprecipitation, cell transfection with RNA + dsDNA, IFN-β reporter assay, cGAS-specific inhibitor control EMBO reports Medium 36382803
2023 cGAS is localized to the outer mitochondrial membrane in hepatocellular carcinoma cells, where it associates with DRP1 to facilitate DRP1 oligomerization; loss of cGAS or DRP1 oligomerization increases mitochondrial ROS and ferroptosis, inhibiting tumor growth. Subcellular fractionation, mitochondrial localization imaging, Co-immunoprecipitation of cGAS-DRP1, ferroptosis assays, in vivo tumor growth experiments Cell research Medium 36864172
2023 ZBP1 stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I IFN signaling; cGAS cooperates with ZBP1 in detecting mitochondrial genome instability. Co-immunoprecipitation of ZBP1-cGAS-RIPK1-RIPK3 complex, ZBP1/cGAS knockout mice, Z-DNA immunofluorescence, STAT1 phosphorylation assays, cardiotoxicity mouse model Cell High 37352855
2023 Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia; cGAS gain-of-function in microglia is sufficient to drive ageing-associated transcriptional states, neurodegeneration, and cognitive decline via STING. cGAS gain-of-function mouse model, single-nucleus RNA-sequencing, STING blockade experiments, mitochondrial DNA isolation, cognitive behavioral tests Nature High 37532932
2023 SIRT2 deacetylates G3BP1 at K257, K276, and K376, causing disassembly of the cGAS-G3BP1 complex, thereby inhibiting cGAS DNA binding and droplet formation and suppressing IFN production; SIRT2 deficiency or inhibition enhances cGAS-STING signaling. Co-immunoprecipitation, deacetylation assays, site-directed mutagenesis (G3BP1 K257/276/376), cGAS droplet formation assays, DNA binding assay, SIRT2 KO/inhibition in cells and mice EMBO reports Medium 37870259
2024 The MRE11-RAD50-NBN complex displaces cGAS from nucleosome acidic-patch-mediated sequestration by binding to nucleosome fragments, enabling cGAS mobilization and activation by dsDNA; MRE11 is essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA, and ionizing radiation, and MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis. Co-immunoprecipitation of MRN complex with nucleosomes and cGAS, MRE11 knockout/depletion, cGAS activation assays, nucleosome displacement assays, necroptosis readouts, breast cancer mouse model Nature High 38200309
2024 The CRL5-SPSB3 ubiquitin ligase complex degrades nuclear cGAS in cycling cells; SPSB3 is the substrate receptor that ligates ubiquitin onto nuclear cGAS via a conserved C-terminal Asn-Asn (NN) degron motif. Cryo-EM structure of nucleosome-bound cGAS in complex with SPSB3 revealed the structural basis. Interference with SPSB3-mediated nuclear cGAS degradation primes cells for type I IFN signaling. Cryo-electron microscopy, ubiquitylation assays, SPSB3 knockout, degron mutagenesis (NN motif), IFN signaling reporter assays, viral infection assays Nature High 38418882
2024 AARS2 associates with cGAS and mediates its lactylation (via AARS1/2 acting as lactyltransferases) at an N-terminal site, abolishing cGAS liquid-like phase separation and DNA sensing; a lactyl-resistant cGAS knock-in protects mice against innate immune evasion induced by high L-lactate. Co-immunoprecipitation of AARS2-cGAS, in vitro lactylation assay, genetic code expansion for lactyl-lysine incorporation, phase separation assays, knock-in mouse models, in vitro DNA sensing assays Nature High 39322678
2024 HERC5 catalyzes ISGylation of cGAS at K21, K187, K219, and K458; ISGylation promotes DNA-induced cGAS oligomerization and enhances cGAS enzymatic activity. USP18 removes ISGylation from cGAS. ISGylation deficiency attenuates IFN expression and antiviral defense. ISGylation assay, site-directed mutagenesis (K21/187/219/458), cGAS oligomerization assay, HERC5/ISG15 KO mouse and cell models, viral infection assays Cell reports Medium 38421872
2020 Cancer cells produce cGAMP that is transferred via gap junctions to tumor-associated dendritic cells and macrophages, which respond by producing type I IFN in situ; cancer-cell-intrinsic cGAS (but not STING) expression promotes CD8+ T cell infiltration and tumor immunogenicity. Gap junction blockade experiments, cGAS/STING-specific knockout in cancer cells, co-culture assays, in vivo tumor models, immune cell infiltration analysis Cell reports Medium 31665636

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 1400 28738408
2019 DNA sensing by the cGAS-STING pathway in health and disease. Nature reviews. Genetics 1198 31358977
2019 Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature 1056 30842662
2019 cGAS in action: Expanding roles in immunity and inflammation. Science (New York, N.Y.) 890 30846571
2017 cGAS is essential for cellular senescence. Proceedings of the National Academy of Sciences of the United States of America 831 28533362
2013 Structural mechanism of cytosolic DNA sensing by cGAS. Nature 742 23722159
2023 cGAS-STING drives ageing-related inflammation and neurodegeneration. Nature 732 37532932
2018 Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 538 30356214
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
2016 The cGAS-STING Defense Pathway and Its Counteraction by Viruses. Cell host & microbe 355 26867174
2019 The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death. Cell 346 31299200
2022 Cellular functions of cGAS-STING signaling. Trends in cell biology 343 36437149
2014 Cytosolic RNA:DNA hybrids activate the cGAS-STING axis. The EMBO journal 296 25425575
2020 cGAS-STING pathway in cancer biotherapy. Molecular cancer 288 32887628
2024 AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases. Nature 277 39322678
2019 Regulation of cGAS- and RLR-mediated immunity to nucleic acids. Nature immunology 273 31819255
2020 Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and Aging. Trends in neurosciences 255 33187730
2018 G3BP1 promotes DNA binding and activation of cGAS. Nature immunology 254 30510222
2019 Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity. Cell reports 238 31665636
2017 Evolutionary Origins of cGAS-STING Signaling. Trends in immunology 227 28416447
2020 Structural mechanism of cGAS inhibition by the nucleosome. Nature 223 32911482
2023 Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity. Cell 211 37352855
2021 Phosphorylation and chromatin tethering prevent cGAS activation during mitosis. Science (New York, N.Y.) 204 33542149
2020 PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity. Science translational medicine 199 32641491
2020 Structural basis of nucleosome-dependent cGAS inhibition. Science (New York, N.Y.) 196 32913000
2020 The interactions between cGAS-STING pathway and pathogens. Signal transduction and targeted therapy 183 32532954
2021 ER-directed TREX1 limits cGAS activation at micronuclei. Molecular cell 166 33476576
2025 Regulation of cGAS-STING signalling and its diversity of cellular outcomes. Nature reviews. Immunology 156 39774812
2020 Crosstalk between cGAS-STING signaling and cell death. Cell death and differentiation 146 32948836
2023 Mitochondria-localized cGAS suppresses ferroptosis to promote cancer progression. Cell research 145 36864172
2013 The cGAS-STING pathway for DNA sensing. Molecular cell 144 23870141
2021 The cGAS-STING Pathway: A Promising Immunotherapy Target. Frontiers in immunology 135 34956229
2018 SnapShot: CGAS-STING Signaling. Cell 133 29570996
2021 Two cGAS-like receptors induce antiviral immunity in Drosophila. Nature 120 34261128
2016 DNA sensor cGAS-mediated immune recognition. Protein & cell 116 27696330
1999 Dopamine D4 receptor gene: novelty or nonsense? Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 116 10379515
2024 MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis. Nature 111 38200309
2020 DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity. Nature communications 109 33273464
2022 The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity. Frontiers in immunology 108 35095914
2023 Bacteriophages inhibit and evade cGAS-like immune function in bacteria. Cell 107 36750095
2021 The role of cGAS-STING signalling in liver diseases. JHEP reports : innovation in hepatology 103 34381984
2023 Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence. Nature 97 36848932
2014 Recognition of cytosolic DNA by cGAS and other STING-dependent sensors. European journal of immunology 97 24356864
2023 Significance of the cGAS-STING Pathway in Health and Disease. International journal of molecular sciences 93 37686127
2010 The dopamine D4 receptor: biochemical and signalling properties. Cellular and molecular life sciences : CMLS 91 20165900
2022 ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation. The EMBO journal 86 35438208
2019 cGAS and CD-NTase enzymes: structure, mechanism, and evolution. Current opinion in structural biology 85 31593902
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
2022 cGAS-STING signaling. Current biology : CB 76 35820380
2020 Regulation and Consequences of cGAS Activation by Self-DNA. Trends in cell biology 74 32546434
2021 The cGAS-STING Pathway: Novel Perspectives in Liver Diseases. Frontiers in immunology 73 33995425
2023 PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity. Nature communications 72 37193698
2023 cGAS-STING signaling in the tumor microenvironment. Cancer letters 68 37748723
2022 Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS. Molecular cell 68 35460603
2021 CGAS is a micronucleophagy receptor for the clearance of micronuclei. Autophagy 68 33752561
2020 Conserved strategies for pathogen evasion of cGAS-STING immunity. Current opinion in immunology 66 32339908
1998 Dopamine D2 and D4 receptor ligands: relation to antipsychotic action. European journal of pharmacology 62 9721018
2019 Neuroinflammation and the cGAS-STING pathway. Journal of neurophysiology 61 30673358
2022 cGAS/STING cross-talks with cell cycle and potentiates cancer immunotherapy. Molecular therapy : the journal of the American Society of Gene Therapy 60 35121107
2022 Nanodelivery of cGAS-STING activators for tumor immunotherapy. Trends in pharmacological sciences 58 36089410
2023 Mn-based cGAS-STING activation for tumor therapy. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 57 36910853
2023 Regulation of cGAS and STING signaling during inflammation and infection. The Journal of biological chemistry 55 37247757
2017 cGAS Conducts Micronuclei DNA Surveillance. Trends in cell biology 52 28882413
2024 The CRL5-SPSB3 ubiquitin ligase targets nuclear cGAS for degradation. Nature 51 38418882
2021 Nuclear cGAS: guard or prisoner? The EMBO journal 51 34250619
2020 cGAS-STING pathway in oncogenesis and cancer therapeutics. Oncotarget 51 32774773
2024 Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma. The Journal of clinical investigation 50 38226619
2021 The cGAS-STING pathway: more than fighting against viruses and cancer. Cell & bioscience 50 34906241
2024 Agonists and Inhibitors of the cGAS-STING Pathway. Molecules (Basel, Switzerland) 49 38999073
2023 Bacterial cGAS senses a viral RNA to initiate immunity. Nature 49 37968393
2021 Nuclear cGAS: sequestration and beyond. Protein & cell 48 34374004
2020 Regulation and inhibition of the DNA sensor cGAS. EMBO reports 48 33155371
2023 Phase-separated nucleocapsid protein of SARS-CoV-2 suppresses cGAS-DNA recognition by disrupting cGAS-G3BP1 complex. Signal transduction and targeted therapy 46 37100798
2022 UXT attenuates the CGAS-STING1 signaling by targeting STING1 for autophagic degradation. Autophagy 46 35543189
2021 The role of cGAS/STING in intestinal immunity. European journal of immunology 46 33577080
2020 Targeting of the cGAS-STING system by DNA viruses. Biochemical pharmacology 45 32004549
2024 Tumor Exosomal ENPP1 Hydrolyzes cGAMP to Inhibit cGAS-STING Signaling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 43 38498770
2019 The cGAS Paradox: Contrasting Roles for cGAS-STING Pathway in Chromosomal Instability. Cells 43 31658669
2016 The role of cGAS in innate immunity and beyond. Journal of molecular medicine (Berlin, Germany) 43 27154323
2024 cGAS/STING signalling pathway in senescence and oncogenesis. Seminars in cancer biology 41 39222763
2025 MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction. Molecular cell 40 40614706
2020 cGAS/STING: novel perspectives of the classic pathway. Molecular biomedicine 40 35006429
2023 Updated roles of cGAS-STING signaling in autoimmune diseases. Frontiers in immunology 39 37781360
2021 Activation of cGAS/STING pathway upon paramyxovirus infection. iScience 39 34142033
2022 Cancer immunotherapy strategies that target the cGAS-STING pathway. Frontiers in immunology 38 36353640
2024 HERC5-catalyzed ISGylation potentiates cGAS-mediated innate immunity. Cell reports 35 38421872
2022 Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner. The Journal of experimental medicine 35 36346347
2022 Control of innate immunity by the cGAS-STING pathway. Immunology and cell biology 34 35485309
2022 Regulation of cGAS activity by RNA-modulated phase separation. EMBO reports 34 36382803
2023 Function and regulation of cGAS-STING signaling in infectious diseases. Frontiers in immunology 31 36825026
2022 Dysregulation of the cGAS-STING Pathway in Monogenic Autoinflammation and Lupus. Frontiers in immunology 31 35693769
2022 Centromere defects, chromosome instability, and cGAS-STING activation in systemic sclerosis. Nature communications 31 36400785
2023 SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1. EMBO reports 30 37870259
2022 EZH2-CCF-cGAS Axis Promotes Breast Cancer Metastasis. International journal of molecular sciences 30 35163710
2022 The multifaceted functions of cGAS. Journal of molecular cell biology 30 35536585
2022 cGAS and cancer therapy: a double-edged sword. Acta pharmacologica Sinica 29 35042992
2022 Advances in cGAS-STING Signaling Pathway and Diseases. Frontiers in cell and developmental biology 29 35186921
2020 The cGAS-STING Pathway in Hematopoiesis and Its Physiopathological Significance. Frontiers in immunology 29 33329537

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