Affinage

CGAS

Cyclic GMP-AMP synthase · UniProt Q8N884

Length
522 aa
Mass
58.8 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

cGAS (cyclic GMP-AMP synthase) is a cytosolic and nuclear DNA sensor that catalyzes the synthesis of the second messenger 2'3'-cGAMP upon binding double-stranded DNA, RNA:DNA hybrids, or mitochondrial DNA, thereby activating the STING–type I interferon axis and STING-dependent autophagy to mediate innate immune defense, cellular senescence, and inflammatory signaling (PMID:23722159, PMID:25425575, PMID:30842662, PMID:28533362). Structural studies revealed that cGAS is held inactive on nuclear chromatin through sequestration by the nucleosome acidic patch, which blocks DNA-binding surface B and prevents the oligomerization required for catalytic activation; release from this tethered state—by micronuclear envelope rupture, MRE11-mediated displacement at DNA damage sites, or mitotic hyperphosphorylation by Aurora kinase B—gates cGAS activation in a context-dependent manner (PMID:32911482, PMID:32913000, PMID:33542149, PMID:38200309, PMID:28738408). cGAS enzymatic activity is further tuned by an array of post-translational modifications including palmitoylation (ZDHHC18), PARylation (PARP1), arginine methylation (PRMT1), lysine lactylation (AARS2), ISGylation (HERC5), phosphorylation (DNA-PK), and proteasomal degradation via CRL5-SPSB3, while G3BP1 promotes activating phase-separated cGAS–DNA condensates (PMID:35438208, PMID:35460603, PMID:37193698, PMID:39322678, PMID:38421872, PMID:33273464, PMID:38418882, PMID:30510222). Beyond innate immunity, cGAS suppresses homologous recombination by interacting with PARP1 at double-strand breaks, functions as a micronucleophagy receptor via its LIR–LC3B interaction, cooperates with ZBP1 to sense Z-form mitochondrial DNA, and associates with mitochondrial DRP1 to regulate mitochondrial dynamics (PMID:30356214, PMID:33752561, PMID:37352855, PMID:36864172).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2013 High

    The first crystal structures of cGAS alone and with substrates established how DNA binding induces a conformational switch that opens the catalytic pocket for cGAMP synthesis, revealing a zinc-thumb DNA recognition element and evolutionary kinship with OAS1.

    Evidence X-ray crystallography of cGAS ± DNA/ATP/GTP complexes with mutagenesis and in vitro enzymatic assays

    PMID:23722159

    Open questions at the time
    • No structure of full-length cGAS with physiological DNA lengths
    • Mechanism of cGAS oligomerization on long DNA not yet resolved
    • In vivo relevance of zinc-thumb mutations not tested
  2. 2014 High

    Demonstration that cGAS directly recognizes RNA:DNA hybrids expanded the ligand repertoire beyond dsDNA, showing that hybrid nucleic acids produced during retroviral replication or R-loop formation are bona fide cGAS agonists.

    Evidence In vitro cGAS enzymatic assay with RNA:DNA hybrids; THP-1 CRISPR KO cells confirming cGAS-STING dependence

    PMID:25425575

    Open questions at the time
    • Structural basis for RNA:DNA hybrid recognition unknown
    • Relative potency versus dsDNA in physiological concentrations not quantified
  3. 2017 High

    Two studies established that cGAS senses self-DNA through micronuclei arising from chromosomal mis-segregation and damaged DNA foci, linking genome instability to innate immune activation and the senescence-associated secretory phenotype (SASP).

    Evidence Live-cell imaging of cGAS on ruptured micronuclei; cGAS-KO MEFs abolishing SASP after DNA damage; laser microdissection with single-cell transcriptomics

    PMID:28533362 PMID:28738408

    Open questions at the time
    • How cGAS distinguishes micronuclear chromatin from bulk nuclear chromatin was unexplained
    • Relative contribution of micronuclei vs. cytosolic DNA fragments to SASP not resolved
  4. 2018 High

    Discovery that nuclear cGAS suppresses homologous recombination by binding PARP1 via poly(ADP-ribose) and blocking PARP1–Timeless interaction established a DNA-repair-suppressive function independent of cGAMP signaling, while BLK-mediated Y215 phosphorylation was shown to retain cGAS in the cytosol.

    Evidence Co-IP, importin-α pulldown, kinase assays, HR repair assays, and in vivo xenograft validation

    PMID:30356214

    Open questions at the time
    • Whether HR suppression is physiologically relevant in normal cells vs. cancer
    • Structural basis of cGAS–PARP1–PAR interaction not determined
  5. 2018 High

    Identification of G3BP1 as a cofactor that promotes large cGAS–DNA condensates revealed that phase-separation-like assembly amplifies cGAS activation, providing a mechanistic link between stress granule biology and innate immune sensing.

    Evidence Reciprocal Co-IP, G3BP1 KO cells, in vitro cGAS DNA-binding and activity assays, EGCG pharmacological disruption

    PMID:30510222

    Open questions at the time
    • Whether G3BP1-cGAS interaction is direct or RNA/DNA-bridged in vivo
    • Role of other G3BP family members not fully assessed
  6. 2019 High

    Two key findings reframed cGAS-STING signaling beyond interferon induction: STING was shown to activate autophagy through COP-II/ERGIC independently of TBK1/interferon, and nucleosome competition was found to gate cGAS activation during normal mitosis while prolonged mitotic arrest allows cGAS-IRF3-dependent apoptosis.

    Evidence Biochemical reconstitution of STING-autophagy with genetic KO panel; in vitro nucleosome competition assays and mitotic arrest/apoptosis models including xenograft

    PMID:30842662 PMID:31299200

    Open questions at the time
    • How low-level cGAS activity during mitotic arrest escapes nucleosome suppression not fully explained
    • Physiological significance of STING-autophagy vs. IFN arm not quantified in vivo
  7. 2020 High

    Three independent cryo-EM structures of cGAS bound to nucleosomes revealed the structural basis of nuclear cGAS silencing: cGAS uses conserved arginines to dock on the H2A-H2B acidic patch, which occludes DNA-binding site B and sterically prevents the 2:2 cGAS–dsDNA dimer required for catalysis.

    Evidence Cryo-EM structures (3.1–3.3 Å) from three independent groups with mutagenesis and competitive binding/activity assays

    PMID:32911480 PMID:32911482 PMID:32913000

    Open questions at the time
    • How chromatin remodelers or histone modifications modulate cGAS–nucleosome affinity in vivo
    • Whether nucleosome tethering serves functions beyond silencing (e.g., positioning for activation)
  8. 2020 High

    DNA-PK was identified as a kinase that directly phosphorylates cGAS to suppress its enzymatic activity, revealing a feedback axis where DNA damage repair machinery restrains innate immune activation.

    Evidence In vitro kinase assay, DNA-PKcs KO mice and patient PRKDC-mutant cells showing enhanced cGAS-dependent inflammatory gene expression

    PMID:33273464

    Open questions at the time
    • Specific cGAS phosphorylation sites mediating suppression not fully mapped
    • Interplay between DNA-PK and Aurora B phosphorylation events unclear
  9. 2021 High

    Mitotic suppression of cGAS was shown to operate through dual mechanisms—N-terminal hyperphosphorylation by Aurora kinase B blocking chromatin sensing, and prevention of cGAS oligomerization on chromatin—explaining how exposed chromosomal DNA avoids activating innate immunity during cell division.

    Evidence In vitro kinase assays identifying Aurora B sites, cell-cycle synchronization, mutagenesis of phosphorylation sites

    PMID:33542149

    Open questions at the time
    • Phosphatase(s) responsible for re-activation after mitotic exit not identified
    • Whether other mitotic kinases contribute additively not resolved
  10. 2021 High

    The discovery that cGAS acts as a selective autophagy receptor for micronuclei through a direct LIR–LC3B interaction established a negative-feedback loop whereby cGAS-mediated micronucleophagy clears the very DNA structures that activate it, limiting cGAMP production.

    Evidence Co-IP of cGAS–LC3B, LIR motif mutagenesis, LC3 recruitment to micronuclei, and cGAMP quantification after genotoxic stress

    PMID:33752561

    Open questions at the time
    • Whether autophagy receptor function requires cGAS catalytic activity
    • Relative contribution of micronucleophagy vs. TREX1 degradation in resolving micronuclear DNA
  11. 2021 High

    TREX1 was shown to antagonize cGAS activation at micronuclei by degrading micronuclear DNA upon ER-mediated access to ruptured micronuclei, establishing TREX1 ER-tethering as critical for spatially targeted nuclease activity.

    Evidence Micronuclei purification, TREX1 localization and ER-tethering mutant analysis, cGAS activation measurement

    PMID:33476576

    Open questions at the time
    • Kinetics of TREX1 vs. cGAS access to ruptured micronuclei not quantified
    • Other nucleases that may cooperate with TREX1 not assessed
  12. 2021 High

    Collided ribosomes were found to directly bind and co-activate cGAS, linking translation stress and ribosome quality control failure to innate immune activation and revealing an unexpected non-nucleic-acid co-activator of cGAS.

    Evidence In vitro cGAS activity assay with purified ribosomes, RQC pathway genetic perturbation, co-sedimentation of cGAS with collided ribosomes

    PMID:34111399

    Open questions at the time
    • Structural basis for ribosome–cGAS interaction not determined
    • Whether ribosome binding activates cGAS independently of DNA or only potentiates DNA-dependent activity
  13. 2022 High

    Identification of ZDHHC18-mediated palmitoylation at C474 and PARP1-mediated PARylation at D191 as inhibitory post-translational modifications of cGAS expanded the repertoire of negative regulatory inputs, both acting by disrupting cGAS–DNA interaction.

    Evidence In vitro palmitoylation/PARylation assays, site-directed mutagenesis, Zdhhc18 KO mice, DNA-PK-dependent PARP1 cytoplasmic translocation, antiviral challenge

    PMID:35438208 PMID:35460603

    Open questions at the time
    • Whether palmitoylation and PARylation are coordinated or independent
    • Depalmitoylating enzyme for cGAS not identified
  14. 2023 High

    Three studies broadened the functional landscape: PRMT1-mediated R133 methylation suppresses cGAS dimerization in tumors; ZBP1 cooperates with cGAS to sense Z-form mitochondrial DNA through a ZBP1-cGAS-RIPK1-RIPK3 complex; and cGAS-STING activation in aged microglia by mitochondrial DNA drives neurodegeneration and cognitive decline.

    Evidence In vitro methyltransferase assays and tumor models (PRMT1); Co-IP of ZBP1-cGAS-RIPK complex with ZBP1 KO mice and doxorubicin cardiotoxicity model; snRNA-seq and cGAS gain-of-function mouse model with cognitive testing

    PMID:37193698 PMID:37352855 PMID:37532932

    Open questions at the time
    • Whether PRMT1 methylation occurs constitutively or is signal-regulated
    • Which cell types beyond microglia show age-dependent cGAS activation in the CNS
    • Structural basis of ZBP1–cGAS cooperativity unknown
  15. 2023 Medium

    Antecedent chromatin modifications (H3K79me2) were found to regulate cGAS recruitment to ruptured micronuclei, indicating that the epigenetic state of mis-segregated chromosomes determines whether they trigger innate immune sensing.

    Evidence ChIP/immunofluorescence for H3K79me2 in micronuclei, acidic patch mutant analysis, IFN signaling reporters

    PMID:36732527

    Open questions at the time
    • Whether other histone marks similarly regulate cGAS recruitment
    • Mechanism by which H3K79me2 facilitates cGAS tethering not structurally resolved
    • Single-lab finding awaiting independent replication
  16. 2023 Medium

    cGAS was shown to localize to the outer mitochondrial membrane where it promotes DRP1 oligomerization and mitochondrial fission, linking cGAS to mitochondrial dynamics and ferroptosis regulation independently of its canonical signaling role.

    Evidence Subcellular fractionation, Co-IP of cGAS–DRP1, DRP1 oligomerization assay, ROS/ferroptosis measurement, in vivo tumor model

    PMID:36864172

    Open questions at the time
    • Mechanism of cGAS mitochondrial targeting not identified
    • Whether this function requires DNA binding or catalytic activity
    • Independent replication needed
  17. 2024 High

    Three discoveries in 2024 revealed new regulatory layers: AARS2-catalyzed lactylation of the cGAS N-terminus abolishes phase separation and DNA sensing, providing a metabolic brake; the CRL5-SPSB3 E3 ligase targets nuclear cGAS for proteasomal degradation via a C-terminal NN degron resolved by cryo-EM; and MRE11 displaces cGAS from nucleosome sequestration at DSBs to enable activation and necroptotic signaling.

    Evidence In vitro lactylation reconstitution and lactyl-resistant knock-in mice (AARS2); cryo-EM of nucleosome–cGAS–SPSB3 complex with ubiquitylation and antiviral assays; nucleosome displacement assays and MRE11 KO with necroptosis readouts and mammary tumor models

    PMID:38200309 PMID:38418882 PMID:39322678

    Open questions at the time
    • Whether AARS2 lactylation is reversible and which delactylase acts on cGAS
    • How SPSB3-mediated degradation is regulated during infection
    • Whether MRE11 displacement generalizes beyond ionizing radiation and oncogenic stress
  18. 2024 High

    HERC5-mediated ISGylation at multiple lysines was shown to promote cGAS oligomerization and enhance enzymatic activation, constituting a positive-feedback amplification loop within the interferon response.

    Evidence In vitro ISGylation assay, multi-site mutagenesis, cGAS oligomerization assay, Isg15/Herc6 KO mice with viral challenge

    PMID:38421872

    Open questions at the time
    • Structural basis for how ISGylation promotes oligomerization not determined
    • Kinetics of ISGylation vs. other PTMs during infection not compared

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how the multiple inhibitory and activating post-translational modifications are temporally coordinated during infection and sterile inflammation; the structural basis of cGAS activation on physiological-length DNA in the context of phase-separated condensates; and whether non-canonical functions (HR suppression, DRP1 regulation, micronucleophagy) operate through shared or independent cGAS conformational states.
  • Integrated PTM code for cGAS regulation not established
  • No full-length cGAS structure on long DNA in condensate form
  • Structural basis distinguishing canonical vs. non-canonical cGAS functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0009975 cyclase activity 2 GO:0098772 molecular function regulator activity 2 GO:0038024 cargo receptor activity 1
Localization
GO:0005694 chromosome 6 GO:0005634 nucleus 5 GO:0005829 cytosol 4 GO:0005739 mitochondrion 2
Pathway
R-HSA-168256 Immune System 7 R-HSA-392499 Metabolism of proteins 6 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
ZBP1-cGAS-RIPK1-RIPK3 complexcGAS-DNA phase-separated condensate

Evidence

Reading pass · 28 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 cyclic dinucleotide (cGAMP) formation via a DNA-induced structural switch, possesses a unique zinc thumb that recognizes B-form dsDNA, and shares structural similarity with the dsRNA sensor OAS1, mechanistically unifying dsRNA and dsDNA innate immune sensing. X-ray crystallography, in vitro enzymatic assays, mutagenesis Nature High 23722159
2019 STING activates autophagy through a TBK1- and interferon-independent mechanism: upon binding cGAMP, STING translocates to the ERGIC via COP-II and ARF GTPases, and STING-containing ERGIC serves as a membrane source for LC3 lipidation in an ATG5/WIPI2-dependent but ULK/VPS34-independent manner, enabling clearance of cytosolic DNA and viruses. Biochemical reconstitution, genetic knockout (TBK1, ATG5, WIPI2, ULK, VPS34), live-cell imaging, functional autophagic clearance assays Nature High 30842662
2017 cGAS localizes to micronuclei arising from genome instability after mitotic mis-segregation; breakdown of the micronuclear envelope leads to rapid cGAS accumulation on chromatin in the micronucleus, activating cGAS and inducing interferon-stimulated gene expression in a cell-cycle-dependent manner. Live-cell imaging, laser microdissection combined with single-cell transcriptomics, mouse model of monogenic autoinflammation, exogenous DNA damage assays Nature High 28738408
2017 cGAS is essential for cellular senescence and the senescence-associated secretory phenotype (SASP): cGAS deletion abrogates SASP induced by spontaneous immortalization or DNA-damaging agents, and cGAS localizes to cytoplasmic foci containing damaged DNA following DNA damage, whereas it associates with chromatin during mitosis in proliferating cells. cGAS knockout MEFs, radiation/etoposide treatment, immunofluorescence localization, SASP cytokine measurement PNAS High 28533362
2018 Nuclear cGAS suppresses homologous recombination (HR)-mediated DNA repair: DNA damage induces importin-α-dependent nuclear translocation of cGAS; B-lymphoid tyrosine kinase (BLK) phosphorylates cGAS at Y215 to promote its cytosolic retention; nuclear cGAS is recruited to DSBs where it interacts with PARP1 via poly(ADP-ribose), and the cGAS-PARP1 interaction impedes PARP1-Timeless complex formation, suppressing HR. Co-immunoprecipitation, importin-α pulldown, kinase assay (BLK phosphorylation of Y215), HR repair assays, knockdown/overexpression in vitro and in vivo xenograft models Nature High 30356214
2018 G3BP1 physically interacts with cGAS and promotes formation of large cGAS-DNA complexes, enhancing DNA binding and cGAS activation; G3BP1 deficiency impairs cGAS-dependent IFN production, and the G3BP1 inhibitor EGCG disrupts G3BP1-cGAS complexes and blocks DNA-induced cGAS activation. Co-IP, pulldown, in vitro cGAS activity assays, G3BP1 knockout cells, mouse model (AGS), patient-derived cells Nature immunology High 30510222
2020 Cryo-EM structures of human cGAS bound to nucleosomes revealed that cGAS contacts both the acidic patch of histone H2A-H2B and nucleosomal DNA; nucleosome binding locks cGAS into an inactive monomer through steric hindrance that suppresses activation by genomic DNA; mutations at the cGAS–acidic patch interface abolish nucleosomal inhibition and unleash cGAS activity on genomic DNA. Cryo-EM structure determination, in vitro biochemical assays, mutagenesis, cell-based cGAS activity assays Nature High 32911482
2020 A second cryo-EM structure of cGAS bound to the nucleosome core particle showed that cGAS uses two conserved arginines to anchor to the nucleosome acidic patch, exclusively occupying the strong dsDNA-binding surface on cGAS and sterically preventing cGAS oligomerization into the functionally active 2:2 cGAS-dsDNA state. Cryo-EM structure (3.3 Å resolution), in vitro binding and activity assays, mutagenesis Science High 32913000
2020 A third cryo-EM structure of cGAS bound to nucleosomes showed that cGAS interacts with histone H2A-H2B via the acidic patch without contacting nucleosomal DNA, burying the cGAS DNA-binding site B and blocking active cGAS dimer formation; the acidic patch robustly outcompetes agonistic DNA for cGAS binding, enabling inhibition even near actively transcribed genomic DNA. Cryo-EM structure, competitive binding assays, in vitro cGAS activity assays Nature High 32911480
2021 During mitosis, cGAS is suppressed by two parallel mechanisms: (1) hyperphosphorylation of cGAS N-terminus by mitotic kinases including Aurora kinase B, which blocks chromatin (but not mitochondrial DNA) sensing; and (2) prevention of oligomerization of chromatin-bound cGAS, which is required for its activation. Biochemical fractionation, in vitro kinase assays, mutagenesis, cell-cycle synchronization experiments Science High 33542149
2014 Cytosolic RNA:DNA hybrids directly activate cGAS: recombinant cGAS produces cGAMP upon RNA:DNA hybrid binding in vitro, and recognition of cytosolic RNA:DNA hybrids in THP-1 cells is completely attributable to the cGAS-STING pathway. In vitro cGAS enzymatic assay with RNA:DNA hybrids, THP-1 CRISPR knockout cells, IFN reporter assays The EMBO journal High 25425575
2019 Nucleosomes competitively inhibit DNA-dependent cGAS activation; during normal mitosis, cGAS-STING is not effectively activated; during mitotic arrest, low-level cGAS-dependent IRF3 phosphorylation accumulates and—independently of IRF3's DNA-binding domain—triggers apoptosis by alleviating Bcl-xL-mediated suppression of mitochondrial outer membrane permeabilization. In vitro nucleosome competition assay, cell-cycle arrest experiments, apoptosis assays, IRF3 domain mutants, xenograft mouse model Cell High 31299200
2021 ER-associated nuclease TREX1 inhibits cGAS activation at micronuclei by degrading micronuclear DNA upon micronuclear envelope rupture; the ER accesses ruptured micronuclei to enable TREX1 nucleolytic attack; TREX1 mutations that untether it from the ER disrupt TREX1 localization to micronuclei and enhance cGAS activation. Micronuclei purification, TREX1 localization (immunofluorescence, live imaging), ER access assays, TREX1 mutant analysis, cGAS activation measurement Molecular cell High 33476576
2020 DNA-PK (DNA-PKcs) phosphorylates cGAS and suppresses its enzymatic activity; DNA-PK deficiency reduces cGAS phosphorylation and potentiates antiviral innate immune responses; cells from DNA-PKcs-deficient mice or patients with PRKDC missense mutations exhibit inflammatory gene expression signatures consistent with enhanced cGAS activity. In vitro kinase assay (DNA-PK phosphorylates cGAS), cells from knockout mice and patient samples, viral replication assays, inflammatory gene expression profiling Nature communications High 33273464
2022 ZDHHC18 palmitoylates cGAS at C474, reducing cGAS-dsDNA interaction and inhibiting cGAS dimerization, thereby suppressing its enzymatic activity; dsDNA promotes this palmitoylation modification; Zdhhc18-deficient mice show resistance to DNA virus infection consistent with enhanced cGAS activity. Palmitoylation assay, site-directed mutagenesis (C474), Co-IP, in vitro cGAS activity assay, Zdhhc18 knockout mice, viral infection experiments The EMBO journal High 35438208
2022 PARP1 translocates to the cytoplasm upon DNA virus infection in a DNA-PK (Thr594 phosphorylation)-dependent manner and directly PARylates cGAS at Asp191, inhibiting its DNA-binding ability and suppressing antiviral immunity. Co-IP, in vitro PARylation assay, mutagenesis (Asp191), PARP1 phosphorylation site mapping (Thr594), subcellular fractionation, antiviral assays in vitro and in vivo Molecular cell High 35460603
2023 PRMT1 methylates cGAS at conserved Arg133, preventing cGAS dimerization and suppressing cGAS/STING-dependent innate immune signaling in cancer cells; PRMT1 inhibition or genetic ablation activates cGAS/STING, elevates type I and II IFN responses, and increases tumor-infiltrating lymphocytes. In vitro methyltransferase assay, mutagenesis (Arg133), Co-IP, cGAS dimerization assays, PRMT1 KO/inhibitor in cell lines and in vivo mouse tumor models Nature communications High 37193698
2024 AARS2 (alanyl-tRNA synthetase 2) senses L-lactate and directly catalyzes ATP-dependent lysine lactylation of cGAS; lactylation at a specific cGAS N-terminal site abolishes cGAS liquid-like phase separation and DNA sensing both in vitro and in vivo; lactyl-resistant knock-in mice are protected against innate immune evasion from high L-lactate. Biochemical L-lactate binding assay, in vitro lactylation assay, genetic code expansion for lactyl-lysine incorporation, phase separation assays (in vitro), cGAS activity assays, knock-in mouse models Nature High 39322678
2024 The CRL5-SPSB3 ubiquitin ligase complex targets nuclear cGAS for proteasomal degradation; cryo-EM structure of nucleosome-bound cGAS complexed with SPSB3 reveals a conserved Asn-Asn (NN) degron motif at the cGAS C-terminus that directs SPSB3 recruitment, ubiquitylation, and cGAS protein stability; interference with SPSB3-mediated degradation primes cells for enhanced type I IFN signaling and protection against DNA viruses. Cryo-EM structure, ubiquitylation assay, SPSB3 KO, proteasome inhibitor experiments, antiviral assays Nature High 38418882
2024 MRE11 (within the MRN complex MRE11-RAD50-NBN) is required for cGAS activation by displacing cGAS from acidic-patch-mediated nucleosome sequestration; MRN complex binding to nucleosome fragments enables cGAS mobilization and activation by dsDNA; MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis to suppress oncogenic proliferation. Nucleosome binding/displacement assays, Co-IP, MRE11 KO, cGAS activation assays (cGAMP measurement), ionizing radiation and oncogenic stress models, necroptosis readouts (MLKL phosphorylation), in vivo mammary tumorigenesis Nature High 38200309
2021 cGAS functions as a micronucleophagy receptor: cGAS accumulates in autophagic machinery, directly interacts with MAP1LC3B/LC3B via an LIR (MAP1LC3-interacting region) motif, and this interaction is essential for LC3 recruitment to micronuclei and selective autophagic clearance of micronuclei; cGAS-mediated micronucleophagy blunts cGAMP production induced by genotoxic stress. Co-IP (cGAS-LC3B interaction), LIR motif mutagenesis, autophagy assays (LC3 recruitment, micronuclei clearance), cGAMP measurement, genotoxic stress models Autophagy High 33752561
2023 cGAS localizes to mitochondria and anchors to the outer mitochondrial membrane, where it associates with dynamin-related protein 1 (DRP1) and facilitates DRP1 oligomerization; in the absence of cGAS or DRP1 oligomerization, mitochondrial ROS accumulates and ferroptosis increases, inhibiting tumor growth. Subcellular fractionation, mitochondrial localization (immunofluorescence), Co-IP (cGAS-DRP1), DRP1 oligomerization assay, ROS measurement, ferroptosis assays, in vivo tumor growth Cell research Medium 36864172
2021 Translation stress and collided ribosomes co-activate cGAS: purified ribosomes directly interact with cGAS and stimulate its DNA-dependent activity in vitro; disruption of ribosome-associated protein quality control (RQC) causes cGAS-dependent ISG expression and re-localization of cGAS from nucleus to cytosol; cGAS preferentially binds collided ribosomes in vitro and in vivo. In vitro cGAS activity assay with purified ribosomes, RQC pathway genetic perturbation, cGAS localization (imaging), co-sedimentation/binding assays for collided ribosomes, ISG reporter assays Molecular cell High 34111399
2022 Cytoplasmic RNAs regulate cGAS activity by promoting phase separation of cGAS in vitro and forming complexes with cGAS in cells; in the presence of cytoplasmic dsDNA, RNAs colocalize with phase-separated cGAS-dsDNA condensates and enhance cGAS enzymatic activity when dsDNA is limiting. In vitro phase separation assay, Co-IP (cGAS-RNA), cGAS enzymatic activity assay, cell transfection (RNA+dsDNA co-delivery), IFN-β reporter, cGAS-specific inhibitor control EMBO reports Medium 36382803
2023 ZBP1 stabilizes Z-form mitochondrial DNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I IFN signaling in response to mitochondrial genome instability; this cooperative sensing mechanism contributes to Doxorubicin-induced cardiotoxicity. Co-IP (ZBP1-cGAS-RIPK1-RIPK3 complex), Z-DNA immunofluorescence, ZBP1 and IFN-I pathway knockout mice, Doxorubicin cardiotoxicity model, STAT1 phosphorylation assays Cell High 37352855
2023 Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei: H3K79me2 marks present before DNA damage are retained in ruptured micronuclei and regulate cGAS recruitment; cGAS tethering to the nucleosome acidic patch is necessary for cGAS-dependent IFN signaling from micronuclei. ChIP/immunofluorescence for H3K79me2, cGAS localization to micronuclei, acidic patch mutant analysis, IFN signaling reporter assays, genotoxic stress models Nature communications Medium 36732527
2024 HERC5 (E3 ubiquitin ligase) catalyzes ISGylation of cGAS at K21, K187, K219, and K458; USP18 removes ISGylation from cGAS; HERC5-mediated ISGylation promotes DNA-induced cGAS oligomerization and enhances its enzymatic activity; ISGylation deficiency attenuates cGAS-STING-dependent antiviral immunity. In vitro ISGylation assay, site-directed mutagenesis (multiple K residues), Co-IP (cGAS-HERC5), cGAS oligomerization assay, cGAMP measurement, Isg15/Herc6 KO mice (viral challenge) Cell reports High 38421872
2023 cGAS-STING drives ageing-related neurodegeneration: cytosolic DNA released from perturbed mitochondria activates cGAS in old microglia, triggering reactive microglial transcriptional states, neurodegeneration, and cognitive decline; cGAS gain-of-function in microglia is sufficient to direct ageing-associated neurodegeneration and impaired memory. Single-nucleus RNA-sequencing, cGAS gain-of-function mouse model, STING blockade experiments, mitochondrial DNA release assays, cognitive behavioral tests Nature High 37532932

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 1368 28738408
2019 DNA sensing by the cGAS-STING pathway in health and disease. Nature reviews. Genetics 1170 31358977
2019 Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature 1026 30842662
2019 cGAS in action: Expanding roles in immunity and inflammation. Science (New York, N.Y.) 862 30846571
2017 cGAS is essential for cellular senescence. Proceedings of the National Academy of Sciences of the United States of America 821 28533362
2013 Structural mechanism of cytosolic DNA sensing by cGAS. Nature 729 23722159
2023 cGAS-STING drives ageing-related inflammation and neurodegeneration. Nature 682 37532932
2018 Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 528 30356214
2022 The cGAS-STING pathway and cancer. Nature cancer 485 36510011
2020 cGAS-STING, an important pathway in cancer immunotherapy. Journal of hematology & oncology 477 32571374
2016 The cGAS-STING Defense Pathway and Its Counteraction by Viruses. Cell host & microbe 351 26867174
2019 The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death. Cell 335 31299200
2022 Cellular functions of cGAS-STING signaling. Trends in cell biology 316 36437149
2014 Cytosolic RNA:DNA hybrids activate the cGAS-STING axis. The EMBO journal 293 25425575
2020 cGAS-STING pathway in cancer biotherapy. Molecular cancer 280 32887628
2019 Regulation of cGAS- and RLR-mediated immunity to nucleic acids. Nature immunology 268 31819255
2018 G3BP1 promotes DNA binding and activation of cGAS. Nature immunology 247 30510222
2020 Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and Aging. Trends in neurosciences 243 33187730
2024 AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases. Nature 241 39322678
2019 Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity. Cell reports 238 31665636
2017 Evolutionary Origins of cGAS-STING Signaling. Trends in immunology 223 28416447
2020 Structural mechanism of cGAS inhibition by the nucleosome. Nature 220 32911482
2023 Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity. Cell 200 37352855
2021 Phosphorylation and chromatin tethering prevent cGAS activation during mitosis. Science (New York, N.Y.) 197 33542149
2020 Structural basis for sequestration and autoinhibition of cGAS by chromatin. Nature 196 32911480
2020 PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity. Science translational medicine 194 32641491
2020 Structural basis of nucleosome-dependent cGAS inhibition. Science (New York, N.Y.) 189 32913000
2020 The interactions between cGAS-STING pathway and pathogens. Signal transduction and targeted therapy 177 32532954
2021 ER-directed TREX1 limits cGAS activation at micronuclei. Molecular cell 163 33476576
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