{"gene":"OGA","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2001,"finding":"MGEA5/OGA produces two protein isoforms (130 kDa and 75 kDa) arising from a splice variant lacking a putative acetyltransferase domain. Cell fractionation revealed the 130 kDa protein localizes to the cytoplasm/cytoskeleton while the 75 kDa protein localizes to the nucleus.","method":"Cell fractionation, polyclonal antibody detection, genomic organization analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular fractionation experiment with antibody detection, single lab, two orthogonal methods (fractionation + genomic splice variant mapping)","pmids":["11341771"],"is_preprint":false},{"year":2005,"finding":"NCOAT/OGA is a bifunctional enzyme with both O-GlcNAcase (glycoside hydrolase) activity in its N-terminal domain and histone acetyltransferase (HAT) activity in its C-terminal domain. A zinc finger-like motif in the HAT domain directly binds histone H4 tail (both acetylated and unacetylated) in vitro, is required for efficient acetyltransferase activity, and catalyzes acetyl transfer to lysine 8 of histone H4.","method":"In vitro binding assay, mutagenesis of zinc finger-like motif, acetyltransferase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis and direct binding assay, single lab but multiple orthogonal methods","pmids":["16356930"],"is_preprint":false},{"year":2006,"finding":"C. elegans OGA ortholog oga-1 encodes an active O-GlcNAcase. Knockout of oga-1 accumulates O-GlcNAc on nuclear pores and other proteins, alters Ser/Thr phosphoprotein profiles, increases GSK-3β levels, elevates glycogen and trehalose stores, decreases lipid storage, and augments dauer formation induced by a temperature-sensitive insulin-like receptor mutant — placing O-GlcNAc cycling in the insulin-like signaling pathway controlling nutrient storage.","method":"Genetic knockout (oga-1(ok1207)), epistasis with daf-2 mutant, biochemical assays for glycogen/trehalose/lipid, western blot for O-GlcNAc and phosphoproteins","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with defined metabolic phenotypes, multiple orthogonal biochemical readouts, replicated across two O-GlcNAc cycling mutants","pmids":["16882729"],"is_preprint":false},{"year":2010,"finding":"Human OGA possesses a conserved peptide-recognition groove beyond its GlcNAc-binding site. Structure of a bacterial OGA orthologue revealed this groove; conserved residues lining it in human OGA were mutated and tested for activity on three O-GlcNAcylated substrates (TAB1, FoxO1, CREB) in an in vitro deglycosylation assay, demonstrating a substrate-recognition mechanism involving interactions with protein context beyond the sugar moiety.","method":"Bacterial OGA crystal structure, site-directed mutagenesis of human OGA, in vitro deglycosylation assay with substrate proteins","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of orthologue combined with mutagenesis and in vitro enzymatic assay on multiple substrates, single lab","pmids":["20863279"],"is_preprint":false},{"year":2021,"finding":"OGA is recruited to DNA damage sites via O-GlcNAcylation-dependent mechanisms. The C-terminal pseudo-HAT domain of OGA is required for this recruitment and associates (via protein affinity purification) with DNA repair factors NONO and the Ku70/80 complex. Following DNA damage, NONO and Ku70/80 are O-GlcNAcylated by OGT; OGA subsequently deglycosylates them, and suppression of this deglycosylation prolongs NONO retention at lesions, delays its chromatin degradation, and impairs non-homologous end joining (NHEJ).","method":"Deletion mutant analysis, unbiased protein affinity purification, co-immunoprecipitation, live-cell recruitment assay, NHEJ functional assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal affinity purification identifying binding partners, deletion mutants defining domain requirement, functional NHEJ assay, single lab with multiple orthogonal methods","pmids":["34135314"],"is_preprint":false},{"year":2020,"finding":"OGT O-GlcNAcylates OGA protein. Using a GlcNAc electrophilic probe and 30 OGT TPR domain mutants, 15 'ladder-like' asparagine/aspartate residues spanning TPRs 3–7 and 10–13.5 were identified as affecting OGA O-GlcNAcylation. The OGA N-terminal region and pseudo-HAT domain are not required for its O-GlcNAcylation, indicating OGT interacts with OGA through its catalytic and/or stalk domains.","method":"GlcNAc electrophilic probe fluorescence assay, OGT TPR mutant screen, OGA truncation constructs","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis of 30 OGT mutants with direct substrate labeling assay, single lab","pmids":["33333092"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of the human OGT-OGA complex reveals that a long flexible OGA segment occupies the extended substrate-binding groove of OGT, positioning a serine for O-GlcNAcylation and preventing OGT from modifying other substrates; conversely, OGT disrupts OGA functional dimerization and occludes its active site, establishing mutual inhibition between the two enzymes as a mechanism for O-GlcNAc homeostasis.","method":"Cryo-electron microscopy structure determination of human OGT alone and OGT-OGA complex","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures of both isolated OGT and OGT-OGA complex, revealing atomic-level mechanism with functional interpretation supported by structural data","pmids":["37907462"],"is_preprint":false},{"year":2024,"finding":"A cancer-derived point mutation on OGA's non-catalytic stalk domain aberrantly alters OGA's interactome and preferentially deglycosylates substrates with +2 proline relative to the O-GlcNAcylation site. The primary dysregulated substrate is PDLIM7; deglycosylated PDLIM7 suppresses p53 transcription and promotes MDM2-mediated p53 ubiquitination, while also upregulating actin-rich membrane protrusions and increasing cancer cell motility.","method":"Quantitative proteomics (interactome and substrate profiling), cancer-derived mutant OGA expression, co-immunoprecipitation, immunoblotting for p53/MDM2, cell motility assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — quantitative proteomic substrate profiling combined with mechanistic follow-up (co-IP, functional assays), single lab with multiple orthogonal methods","pmids":["38838015"],"is_preprint":false},{"year":2024,"finding":"RBM14 promotes ubiquitin-dependent proteasomal degradation of OGA protein, thereby elevating cellular O-GlcNAcylation. RBM14 is itself O-GlcNAcylated at serine 521, which regulates its interaction with E3 ligase TRIM33 and consequently affects OGA protein stability. Mutation of S521 to alanine abrogates RBM14 oncogenic properties.","method":"Co-immunoprecipitation, proteasome inhibitor treatment, siRNA knockdown, site-directed mutagenesis (S521A), ubiquitination assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and mutagenesis identifying E3 ligase-substrate relationship, functional rescue experiments, single lab","pmids":["38678556"],"is_preprint":false},{"year":2024,"finding":"UBR5 acts as an E3 ubiquitin ligase that directly binds OGA, facilitating its ubiquitination and proteasomal degradation, thereby increasing O-GlcNAcylation-mediated EMT and gemcitabine resistance in pancreatic cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, UBR5 knockdown with OGA protein level measurement, in vivo xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and ubiquitination assays, in vitro and in vivo validation, single lab","pmids":["38755129"],"is_preprint":false},{"year":2021,"finding":"RANBP2 (SUMO E3 ligase) facilitates SUMOylation and degradation of CEBPα transcription factor; CEBPα directly augments OGA transcription. RANBP2-mediated CEBPα degradation thus downregulates OGA transcription, elevating global O-GlcNAcylation and promoting hepatocellular carcinoma malignancy.","method":"RANBP2-CEBPα co-immunoprecipitation, OGA promoter transcriptional assay, SUMOylation assay, in vitro and in vivo HCC models","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction and transcriptional regulation assays, in vivo validation, single lab with multiple orthogonal methods","pmids":["34298689"],"is_preprint":false},{"year":2022,"finding":"NAT10-mediated ac4C modification on OGA mRNA suppresses its degradation, maintaining OGA mRNA stability and expression. Knockdown of OGA impairs oocyte maturation; as oocytes mature, OGA expression increases while O-GlcNAc levels decrease.","method":"NAT10 knockdown transcriptome analysis, OGA knockdown in oocytes, RNA stability assay, ac4C detection","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — transcriptome-guided identification of ac4C on OGA mRNA, functional knockdown phenotype, single lab","pmids":["35937804"],"is_preprint":false},{"year":2025,"finding":"OGA is present in dendritic spines and promotes spine maturation, increases spine density, alters synapse size, and downregulates GluA2-containing AMPA receptors in developing and mature neurons.","method":"Immunohistochemistry, biochemical fractionation, functional spine morphology assays, AMPAR subunit analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, primarily immunohistochemical and morphological readouts without in-depth mechanistic dissection","pmids":["bio_10.1101_2025.08.15.670533"],"is_preprint":true},{"year":2025,"finding":"Multi-domain OGA structures (crystal structure of Trichoplax adhaerens pHAT domain, cryo-EM of multi-domain T. adhaerens and human OGAs) reveal that the pseudo-HAT (pHAT) domain forms catalytically incompetent symmetric homodimers exposing a putative peptide-binding site. In human OGA, pHAT domain positions allosterically determine the wider active site environment through a conformational change involving a tryptophan in a flexible arm region.","method":"X-ray crystallography (pHAT domain), cryo-EM (multi-domain OGA), surface plasmon resonance, small-angle X-ray scattering","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure and cryo-EM with biophysical validation, preprint not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.03.10.642372"],"is_preprint":true},{"year":2022,"finding":"Bicyclic picomolar thiazolidine inhibitors of human OGA were co-crystallized with OGA, revealing the structural basis for their exceptional potency (inhibitors extend out of the active site cleft). Chemoproteomic pull-down using these inhibitors identified endogenous OGA post-translational modifications including O-ubiquitination and N-formylation.","method":"X-ray crystal structures of inhibitor-OGA complexes, chemoproteomic affinity purification, targeted proteomics","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with functional inhibitor validation and chemoproteomic mapping of endogenous PTMs, multiple orthogonal methods in single study","pmids":["34985906"],"is_preprint":false},{"year":2019,"finding":"OGA substrate specificity toward the sugar moiety was investigated using glycopeptides with chemoenzymatically modified GlcNAc residues prepared by OGT-catalyzed reactions; this in vitro assay revealed the structural requirements of the GlcNAc residue recognized by human OGA.","method":"Chemoenzymatic glycopeptide synthesis, in vitro OGA deglycosylation assay","journal":"Frontiers in chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro assay with limited mechanistic depth, single lab","pmids":["30693278"],"is_preprint":false},{"year":2019,"finding":"Nearby phosphorylation on a ZO-3-derived peptide affects de-O-GlcNAcylation by OGA (though to a lesser extent than phosphorylation affects O-GlcNAcylation by OGT), demonstrating crosstalk between phosphorylation and OGA activity at adjacent sites.","method":"Peptide microarray with OGA activity assay, phosphatase treatment","journal":"Amino acids","confidence":"Low","confidence_rationale":"Tier 3 / Weak — peptide microarray assay in a model system, single lab, no in-cell validation","pmids":["30725225"],"is_preprint":false},{"year":2025,"finding":"OGA deglycosylates NEK7 at T170 and T172; O-GlcNAcylated NEK7 has reduced interaction with NLRP3 (confirmed by co-IP). OGA knockdown increases NEK7 O-GlcNAcylation, weakens NEK7-NLRP3 interaction, inhibits pyroptosis, and reduces motor dysfunction/dopaminergic neurodegeneration in MPTP-treated mice. OGT deficiency abolished protective effects of OGA knockdown.","method":"Co-immunoprecipitation, site-directed mutagenesis (T170A, T172A), OGA knockdown, MPTP mouse model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis at specific O-GlcNAc sites, in vivo epistasis with OGT, single lab","pmids":["41066511"],"is_preprint":false},{"year":2025,"finding":"OGA removes O-GlcNAcylation from ZEB1 at serine 670, decreasing ZEB1 protein stability. Artesunate directly binds OGA (confirmed by molecular docking and biolayer interferometry), induces OGA expression, and OGA knockdown reverses artesunate-mediated inhibition of HCC cell migration and invasion.","method":"Molecular docking, biolayer interferometry, immunoprecipitation, cycloheximide chase assay, OGA knockdown, cell migration/invasion assay","journal":"Open life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay (biolayer interferometry) plus substrate deglycosylation at defined site (S670), functional rescue, single lab","pmids":["40771411"],"is_preprint":false},{"year":2025,"finding":"OGA suppresses O-GlcNAcylation of KLF2 at S177, reducing KLF2 protein stability; OGA knockdown promotes KLF2 O-GlcNAcylation and stability, inhibits senescence, and promotes mitophagy in dental pulp stem cells. KLF2 silencing reverses the effects of OGA knockdown.","method":"Immunoprecipitation, western blotting for O-GlcNAc on KLF2, OGA and KLF2 knockdown, senescence-associated β-galactosidase staining, mitophagy assay","journal":"BMC oral health","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, co-IP-based substrate identification, functional assay without in vitro reconstitution","pmids":["40251583"],"is_preprint":false},{"year":2025,"finding":"OGA inhibitors (ceperognastat, ASN90, MK8719) produce convergent acute synaptotoxic effects in mouse hippocampal slices: suppression of paired-pulse facilitation/depression and long-term potentiation, increased PSD-95, reduced Synaptophysin 1, and a biphasic shift in tau phosphorylation, suggesting a class-wide mechanism of synaptic impairment from OGA inhibition.","method":"Ex vivo hippocampal slice electrophysiology (LTP, paired-pulse), immunohistochemistry for synaptic proteins and tau phosphorylation","journal":"bioRxiv / The journal of prevention of Alzheimer's disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three structurally distinct inhibitors producing convergent electrophysiological phenotypes with molecular marker validation, two independent publications (preprint and peer-reviewed)","pmids":["40654706","41478829"],"is_preprint":false},{"year":2025,"finding":"O-GlcNAc abundance depends on temperature across multiple organisms (Drosophila, zebrafish, mammalian cells). In cultured cells, the OGT/OGA protein ratio changes with temperature. Pharmacological OGA inhibition decoupled the temperature-dependent O-GlcNAc decrease in cultured cells, and an OGA null allele in Drosophila had the same effect, demonstrating that OGA activity is a key driver of temperature-dependent O-GlcNAc reduction.","method":"OGA inhibitor treatment, OGA null allele in Drosophila, temperature manipulation, O-GlcNAc western blotting, OGT/OGA protein quantification","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic null allele plus pharmacological inhibition across multiple organisms and cell systems, preprint","pmids":["bio_10.1101_2025.07.08.660373"],"is_preprint":true}],"current_model":"OGA (MGEA5/NCOAT) is a dimeric, multi-domain glycoside hydrolase that removes O-GlcNAc from serine/threonine residues of hundreds of nuclear and cytoplasmic proteins; its N-terminal catalytic domain recognizes substrates through a conserved peptide-binding groove beyond the GlcNAc-binding site, its C-terminal pseudo-HAT (pHAT) domain forms a regulatory homodimer that allosterically modulates the active site and recruits DNA-damage repair factors (NONO, Ku70/80) for deglycosylation, and OGA itself is subject to regulation by O-GlcNAcylation (via OGT), proteasomal degradation (via UBR5 and RBM14/TRIM33 E3 ligase pathways), and transcriptional control (via CEBPα/RANBP2), while forming a mutual-inhibition complex with OGT that limits futile O-GlcNAc cycling and maintains homeostasis."},"narrative":{"mechanistic_narrative":"OGA (MGEA5/NCOAT) is a multi-domain glycoside hydrolase that removes O-GlcNAc from serine/threonine residues of nuclear and cytoplasmic proteins, opposing the glycosyltransferase OGT to set cellular O-GlcNAc homeostasis [PMID:20863279, PMID:16882729]. Its N-terminal catalytic domain selects substrates not only through the GlcNAc moiety but through a conserved peptide-recognition groove that reads protein context beyond the sugar, as defined for substrates such as TAB1, FoxO1 and CREB [PMID:20863279, PMID:30693278]. The C-terminal pseudo-HAT (pHAT) domain forms catalytically incompetent symmetric homodimers that allosterically tune the active-site environment and serve as a protein-interaction platform [PMID:bio_10.1101_2025.03.10.642372]; through this domain OGA is recruited to DNA-damage sites and deglycosylates the repair factors NONO and Ku70/80 to support non-homologous end joining [PMID:34135314]. OGA and OGT engage in reciprocal inhibition: a flexible OGA segment occupies the OGT substrate groove and is itself O-GlcNAcylated, while OGT disrupts OGA dimerization and occludes its active site, coupling the two enzymes into a homeostatic unit [PMID:37907462, PMID:33333092]. OGA abundance is further controlled post-translationally by ubiquitin-dependent proteasomal degradation through the E3 ligases UBR5 and the RBM14/TRIM33 axis, and transcriptionally via the RANBP2–CEBPα pathway, with loss of OGA elevating global O-GlcNAcylation in cancer contexts [PMID:38755129, PMID:38678556, PMID:34298689]. Through site-specific deglycosylation of diverse substrates—including PDLIM7, ZEB1, KLF2 and NEK7—OGA influences p53 signaling, epithelial-mesenchymal transition, cellular senescence and NLRP3-dependent pyroptosis [PMID:38838015, PMID:40771411, PMID:40251583, PMID:41066511]. Across organisms, OGA cycling links O-GlcNAc to nutrient and insulin-like signaling and is a principal driver of temperature-dependent changes in O-GlcNAc levels [PMID:16882729, PMID:bio_10.1101_2025.07.08.660373].","teleology":[{"year":2001,"claim":"Established that the MGEA5/OGA locus produces distinct protein isoforms with separate subcellular destinations, raising the question of compartment-specific function.","evidence":"Cell fractionation and genomic splice-variant mapping with antibody detection","pmids":["11341771"],"confidence":"Medium","gaps":["Functional consequence of the 75 kDa nuclear isoform not defined","Catalytic activity of each isoform not directly compared"]},{"year":2005,"claim":"Characterized OGA as bifunctional, assigning a putative histone acetyltransferase activity to its C-terminal domain and a zinc-finger motif that binds the histone H4 tail.","evidence":"In vitro binding and acetyltransferase assays with zinc-finger mutagenesis","pmids":["16356930"],"confidence":"High","gaps":["Physiological relevance of HAT activity in cells not established","Later structural work reclassifies this region as a catalytically incompetent pseudo-HAT"]},{"year":2006,"claim":"Placed O-GlcNAc cycling in the insulin-like signaling pathway by showing OGA loss reprograms nutrient storage and modifies dauer formation in C. elegans.","evidence":"oga-1 genetic knockout with daf-2 epistasis and metabolic biochemistry","pmids":["16882729"],"confidence":"High","gaps":["Direct OGA substrates driving the metabolic phenotype not identified","Mammalian generality of the insulin-signaling link not addressed here"]},{"year":2010,"claim":"Resolved how OGA achieves substrate selectivity, identifying a peptide-recognition groove that reads protein context beyond the GlcNAc sugar.","evidence":"Bacterial OGA crystal structure with human OGA mutagenesis and in vitro deglycosylation of TAB1/FoxO1/CREB","pmids":["20863279"],"confidence":"High","gaps":["Structure of the full human enzyme groove not solved here","Sequence determinants of preferred substrates not enumerated"]},{"year":2019,"claim":"Probed the molecular requirements of OGA recognition at the sugar moiety and at adjacent phosphorylation sites, defining crosstalk constraints on de-O-GlcNAcylation.","evidence":"Chemoenzymatic glycopeptide synthesis and peptide-microarray OGA activity assays","pmids":["30693278","30725225"],"confidence":"Low","gaps":["Single in vitro assays without in-cell validation","Effect sizes of phospho-crosstalk modest and substrate-limited"]},{"year":2021,"claim":"Connected OGA to genome maintenance, showing pHAT-dependent recruitment to lesions and deglycosylation of repair factors required for efficient NHEJ.","evidence":"Deletion mutants, affinity purification of NONO and Ku70/80, live-cell recruitment and NHEJ assays","pmids":["34135314"],"confidence":"High","gaps":["Direct structural basis of pHAT-repair factor binding not resolved","Whether OGA acts in other repair pathways not tested"]},{"year":2021,"claim":"Identified transcriptional control of OGA via the RANBP2–CEBPα axis, linking OGA downregulation to elevated O-GlcNAc and hepatocellular carcinoma malignancy.","evidence":"Co-IP, OGA promoter assays, SUMOylation assays, in vivo HCC models","pmids":["34298689"],"confidence":"Medium","gaps":["Direct CEBPα binding sites on the OGA promoter not mapped","Generality beyond HCC unknown"]},{"year":2020,"claim":"Showed OGA is itself an OGT substrate and mapped the OGT TPR residues governing this modification, embedding OGA in a reciprocal modification loop.","evidence":"GlcNAc electrophilic probe assay with a 30-mutant OGT TPR screen and OGA truncations","pmids":["33333092"],"confidence":"Medium","gaps":["Functional consequence of OGA O-GlcNAcylation not established","Modified residues on OGA not pinpointed"]},{"year":2022,"claim":"Provided structural rationale for picomolar OGA inhibitors and used them chemoproteomically to detect endogenous OGA modifications including O-ubiquitination and N-formylation.","evidence":"X-ray structures of inhibitor-OGA complexes and chemoproteomic affinity purification","pmids":["34985906"],"confidence":"High","gaps":["Functional roles of the detected endogenous PTMs not characterized","Inhibitor selectivity across the proteome not fully resolved"]},{"year":2022,"claim":"Defined an RNA-level control of OGA via NAT10-mediated ac4C mRNA stabilization, with functional importance during oocyte maturation.","evidence":"NAT10 knockdown transcriptomics, RNA stability assays, OGA knockdown in oocytes","pmids":["35937804"],"confidence":"Medium","gaps":["Specific ac4C sites on OGA mRNA not pinpointed","Mechanistic link between OGA loss and maturation arrest unresolved"]},{"year":2023,"claim":"Resolved the structural basis of OGT-OGA mutual inhibition, establishing the enzyme pair as a self-limiting homeostatic unit.","evidence":"Cryo-EM of human OGT alone and the OGT-OGA complex","pmids":["37907462"],"confidence":"High","gaps":["Dynamics and regulation of complex assembly in cells not defined","How upstream signals tip the balance not addressed"]},{"year":2024,"claim":"Demonstrated that ubiquitin-dependent degradation of OGA by UBR5 and by the RBM14/TRIM33 axis tunes cellular O-GlcNAc and drives cancer phenotypes.","evidence":"Co-IP, ubiquitination assays, E3 ligase knockdown, mutagenesis, and xenograft models","pmids":["38755129","38678556"],"confidence":"Medium","gaps":["Direct ubiquitination sites on OGA not mapped","Relative contribution of each E3 pathway in normal tissue unknown"]},{"year":2024,"claim":"Showed a cancer-derived stalk-domain mutation reshapes OGA's interactome and substrate preference, with deglycosylated PDLIM7 suppressing p53 and enhancing motility.","evidence":"Quantitative interactome/substrate proteomics, mutant expression, co-IP, and motility assays","pmids":["38838015"],"confidence":"High","gaps":["Frequency and significance of the mutation in patient tumors not quantified","Structural basis for altered +2-proline preference not resolved"]},{"year":2025,"claim":"Identified additional site-specific OGA substrates (NEK7 T170/T172, ZEB1 S670, KLF2 S177) coupling deglycosylation to pyroptosis, EMT, and senescence in distinct disease models.","evidence":"Co-IP, site-directed mutagenesis, knockdown rescue, and in vivo/cellular functional assays","pmids":["41066511","40771411","40251583"],"confidence":"Medium","gaps":["In vitro reconstitution of direct deglycosylation lacking for several substrates","KLF2 finding is Low-confidence and single-lab"]},{"year":2025,"claim":"Defined the multi-domain architecture, showing the pHAT domain forms symmetric homodimers that allosterically shape the active site via a conformational change.","evidence":"X-ray crystallography of the pHAT domain and cryo-EM of multi-domain OGA with SPR/SAXS (preprint)","pmids":["bio_10.1101_2025.03.10.642372"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Ligand or partner occupying the exposed pHAT peptide site not identified"]},{"year":2025,"claim":"Linked OGA activity to neuronal physiology and environmental sensing, implicating it in synaptic maturation, inhibitor-induced synaptotoxicity, and temperature-dependent O-GlcNAc dynamics.","evidence":"Hippocampal slice electrophysiology with structurally distinct inhibitors, spine morphology assays, and OGA null/inhibition across organisms","pmids":["40654706","41478829","bio_10.1101_2025.08.15.670533","bio_10.1101_2025.07.08.660373"],"confidence":"Medium","gaps":["Substrates mediating synaptic and temperature effects not identified","Some findings are preprints or Low-confidence morphology-based readouts"]},{"year":null,"claim":"How OGA substrate selection, dimerization state, and OGT-coupling are dynamically integrated to direct deglycosylation toward specific targets in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking pHAT dimerization, OGT inhibition, and substrate choice in cells","Physiological triggers that redistribute OGA among compartments and partners undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[3,15,7,18,17]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,7]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,6,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,9,10]}],"complexes":["OGT-OGA mutual-inhibition complex","OGA pseudo-HAT homodimer"],"partners":["OGT","NONO","KU70/80","UBR5","RBM14","TRIM33","NEK7","PDLIM7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60502","full_name":"Protein O-GlcNAcase","aliases":["Beta-N-acetylglucosaminidase","Beta-N-acetylhexosaminidase","Beta-hexosaminidase","Meningioma-expressed antigen 5","N-acetyl-beta-D-glucosaminidase","N-acetyl-beta-glucosaminidase","Nuclear cytoplasmic O-GlcNAcase and acetyltransferase","NCOAT"],"length_aa":916,"mass_kda":102.9,"function":"Cleaves GlcNAc but not GalNAc from O-glycosylated proteins (PubMed:11148210, PubMed:11788610, PubMed:20673219, PubMed:22365600, PubMed:24088714, PubMed:28939839, PubMed:37962578). Deglycosylates a large and diverse number of proteins, such as CRYAB, ELK1, GSDMD, LMNB1 and TAB1 (PubMed:28939839, PubMed:37962578). Can use p-nitrophenyl-beta-GlcNAc and 4-methylumbelliferone-GlcNAc as substrates but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro) (PubMed:20673219). Does not bind acetyl-CoA and does not have histone acetyltransferase activity (PubMed:24088714) Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. 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gyrus","date":"2024-09-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.19.613771","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38882,"output_tokens":5857,"usd":0.10225,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14379,"output_tokens":4940,"usd":0.097698,"stage2_stop_reason":"end_turn"},"total_usd":0.199948,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"MGEA5/OGA produces two protein isoforms (130 kDa and 75 kDa) arising from a splice variant lacking a putative acetyltransferase domain. Cell fractionation revealed the 130 kDa protein localizes to the cytoplasm/cytoskeleton while the 75 kDa protein localizes to the nucleus.\",\n      \"method\": \"Cell fractionation, polyclonal antibody detection, genomic organization analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular fractionation experiment with antibody detection, single lab, two orthogonal methods (fractionation + genomic splice variant mapping)\",\n      \"pmids\": [\"11341771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NCOAT/OGA is a bifunctional enzyme with both O-GlcNAcase (glycoside hydrolase) activity in its N-terminal domain and histone acetyltransferase (HAT) activity in its C-terminal domain. A zinc finger-like motif in the HAT domain directly binds histone H4 tail (both acetylated and unacetylated) in vitro, is required for efficient acetyltransferase activity, and catalyzes acetyl transfer to lysine 8 of histone H4.\",\n      \"method\": \"In vitro binding assay, mutagenesis of zinc finger-like motif, acetyltransferase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis and direct binding assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"16356930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"C. elegans OGA ortholog oga-1 encodes an active O-GlcNAcase. Knockout of oga-1 accumulates O-GlcNAc on nuclear pores and other proteins, alters Ser/Thr phosphoprotein profiles, increases GSK-3β levels, elevates glycogen and trehalose stores, decreases lipid storage, and augments dauer formation induced by a temperature-sensitive insulin-like receptor mutant — placing O-GlcNAc cycling in the insulin-like signaling pathway controlling nutrient storage.\",\n      \"method\": \"Genetic knockout (oga-1(ok1207)), epistasis with daf-2 mutant, biochemical assays for glycogen/trehalose/lipid, western blot for O-GlcNAc and phosphoproteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with defined metabolic phenotypes, multiple orthogonal biochemical readouts, replicated across two O-GlcNAc cycling mutants\",\n      \"pmids\": [\"16882729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human OGA possesses a conserved peptide-recognition groove beyond its GlcNAc-binding site. Structure of a bacterial OGA orthologue revealed this groove; conserved residues lining it in human OGA were mutated and tested for activity on three O-GlcNAcylated substrates (TAB1, FoxO1, CREB) in an in vitro deglycosylation assay, demonstrating a substrate-recognition mechanism involving interactions with protein context beyond the sugar moiety.\",\n      \"method\": \"Bacterial OGA crystal structure, site-directed mutagenesis of human OGA, in vitro deglycosylation assay with substrate proteins\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of orthologue combined with mutagenesis and in vitro enzymatic assay on multiple substrates, single lab\",\n      \"pmids\": [\"20863279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OGA is recruited to DNA damage sites via O-GlcNAcylation-dependent mechanisms. The C-terminal pseudo-HAT domain of OGA is required for this recruitment and associates (via protein affinity purification) with DNA repair factors NONO and the Ku70/80 complex. Following DNA damage, NONO and Ku70/80 are O-GlcNAcylated by OGT; OGA subsequently deglycosylates them, and suppression of this deglycosylation prolongs NONO retention at lesions, delays its chromatin degradation, and impairs non-homologous end joining (NHEJ).\",\n      \"method\": \"Deletion mutant analysis, unbiased protein affinity purification, co-immunoprecipitation, live-cell recruitment assay, NHEJ functional assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal affinity purification identifying binding partners, deletion mutants defining domain requirement, functional NHEJ assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34135314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OGT O-GlcNAcylates OGA protein. Using a GlcNAc electrophilic probe and 30 OGT TPR domain mutants, 15 'ladder-like' asparagine/aspartate residues spanning TPRs 3–7 and 10–13.5 were identified as affecting OGA O-GlcNAcylation. The OGA N-terminal region and pseudo-HAT domain are not required for its O-GlcNAcylation, indicating OGT interacts with OGA through its catalytic and/or stalk domains.\",\n      \"method\": \"GlcNAc electrophilic probe fluorescence assay, OGT TPR mutant screen, OGA truncation constructs\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis of 30 OGT mutants with direct substrate labeling assay, single lab\",\n      \"pmids\": [\"33333092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of the human OGT-OGA complex reveals that a long flexible OGA segment occupies the extended substrate-binding groove of OGT, positioning a serine for O-GlcNAcylation and preventing OGT from modifying other substrates; conversely, OGT disrupts OGA functional dimerization and occludes its active site, establishing mutual inhibition between the two enzymes as a mechanism for O-GlcNAc homeostasis.\",\n      \"method\": \"Cryo-electron microscopy structure determination of human OGT alone and OGT-OGA complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures of both isolated OGT and OGT-OGA complex, revealing atomic-level mechanism with functional interpretation supported by structural data\",\n      \"pmids\": [\"37907462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A cancer-derived point mutation on OGA's non-catalytic stalk domain aberrantly alters OGA's interactome and preferentially deglycosylates substrates with +2 proline relative to the O-GlcNAcylation site. The primary dysregulated substrate is PDLIM7; deglycosylated PDLIM7 suppresses p53 transcription and promotes MDM2-mediated p53 ubiquitination, while also upregulating actin-rich membrane protrusions and increasing cancer cell motility.\",\n      \"method\": \"Quantitative proteomics (interactome and substrate profiling), cancer-derived mutant OGA expression, co-immunoprecipitation, immunoblotting for p53/MDM2, cell motility assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomic substrate profiling combined with mechanistic follow-up (co-IP, functional assays), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38838015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM14 promotes ubiquitin-dependent proteasomal degradation of OGA protein, thereby elevating cellular O-GlcNAcylation. RBM14 is itself O-GlcNAcylated at serine 521, which regulates its interaction with E3 ligase TRIM33 and consequently affects OGA protein stability. Mutation of S521 to alanine abrogates RBM14 oncogenic properties.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor treatment, siRNA knockdown, site-directed mutagenesis (S521A), ubiquitination assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and mutagenesis identifying E3 ligase-substrate relationship, functional rescue experiments, single lab\",\n      \"pmids\": [\"38678556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBR5 acts as an E3 ubiquitin ligase that directly binds OGA, facilitating its ubiquitination and proteasomal degradation, thereby increasing O-GlcNAcylation-mediated EMT and gemcitabine resistance in pancreatic cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, UBR5 knockdown with OGA protein level measurement, in vivo xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and ubiquitination assays, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"38755129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RANBP2 (SUMO E3 ligase) facilitates SUMOylation and degradation of CEBPα transcription factor; CEBPα directly augments OGA transcription. RANBP2-mediated CEBPα degradation thus downregulates OGA transcription, elevating global O-GlcNAcylation and promoting hepatocellular carcinoma malignancy.\",\n      \"method\": \"RANBP2-CEBPα co-immunoprecipitation, OGA promoter transcriptional assay, SUMOylation assay, in vitro and in vivo HCC models\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction and transcriptional regulation assays, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34298689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAT10-mediated ac4C modification on OGA mRNA suppresses its degradation, maintaining OGA mRNA stability and expression. Knockdown of OGA impairs oocyte maturation; as oocytes mature, OGA expression increases while O-GlcNAc levels decrease.\",\n      \"method\": \"NAT10 knockdown transcriptome analysis, OGA knockdown in oocytes, RNA stability assay, ac4C detection\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — transcriptome-guided identification of ac4C on OGA mRNA, functional knockdown phenotype, single lab\",\n      \"pmids\": [\"35937804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OGA is present in dendritic spines and promotes spine maturation, increases spine density, alters synapse size, and downregulates GluA2-containing AMPA receptors in developing and mature neurons.\",\n      \"method\": \"Immunohistochemistry, biochemical fractionation, functional spine morphology assays, AMPAR subunit analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, primarily immunohistochemical and morphological readouts without in-depth mechanistic dissection\",\n      \"pmids\": [\"bio_10.1101_2025.08.15.670533\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Multi-domain OGA structures (crystal structure of Trichoplax adhaerens pHAT domain, cryo-EM of multi-domain T. adhaerens and human OGAs) reveal that the pseudo-HAT (pHAT) domain forms catalytically incompetent symmetric homodimers exposing a putative peptide-binding site. In human OGA, pHAT domain positions allosterically determine the wider active site environment through a conformational change involving a tryptophan in a flexible arm region.\",\n      \"method\": \"X-ray crystallography (pHAT domain), cryo-EM (multi-domain OGA), surface plasmon resonance, small-angle X-ray scattering\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure and cryo-EM with biophysical validation, preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.03.10.642372\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Bicyclic picomolar thiazolidine inhibitors of human OGA were co-crystallized with OGA, revealing the structural basis for their exceptional potency (inhibitors extend out of the active site cleft). Chemoproteomic pull-down using these inhibitors identified endogenous OGA post-translational modifications including O-ubiquitination and N-formylation.\",\n      \"method\": \"X-ray crystal structures of inhibitor-OGA complexes, chemoproteomic affinity purification, targeted proteomics\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with functional inhibitor validation and chemoproteomic mapping of endogenous PTMs, multiple orthogonal methods in single study\",\n      \"pmids\": [\"34985906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OGA substrate specificity toward the sugar moiety was investigated using glycopeptides with chemoenzymatically modified GlcNAc residues prepared by OGT-catalyzed reactions; this in vitro assay revealed the structural requirements of the GlcNAc residue recognized by human OGA.\",\n      \"method\": \"Chemoenzymatic glycopeptide synthesis, in vitro OGA deglycosylation assay\",\n      \"journal\": \"Frontiers in chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro assay with limited mechanistic depth, single lab\",\n      \"pmids\": [\"30693278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nearby phosphorylation on a ZO-3-derived peptide affects de-O-GlcNAcylation by OGA (though to a lesser extent than phosphorylation affects O-GlcNAcylation by OGT), demonstrating crosstalk between phosphorylation and OGA activity at adjacent sites.\",\n      \"method\": \"Peptide microarray with OGA activity assay, phosphatase treatment\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — peptide microarray assay in a model system, single lab, no in-cell validation\",\n      \"pmids\": [\"30725225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OGA deglycosylates NEK7 at T170 and T172; O-GlcNAcylated NEK7 has reduced interaction with NLRP3 (confirmed by co-IP). OGA knockdown increases NEK7 O-GlcNAcylation, weakens NEK7-NLRP3 interaction, inhibits pyroptosis, and reduces motor dysfunction/dopaminergic neurodegeneration in MPTP-treated mice. OGT deficiency abolished protective effects of OGA knockdown.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (T170A, T172A), OGA knockdown, MPTP mouse model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis at specific O-GlcNAc sites, in vivo epistasis with OGT, single lab\",\n      \"pmids\": [\"41066511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OGA removes O-GlcNAcylation from ZEB1 at serine 670, decreasing ZEB1 protein stability. Artesunate directly binds OGA (confirmed by molecular docking and biolayer interferometry), induces OGA expression, and OGA knockdown reverses artesunate-mediated inhibition of HCC cell migration and invasion.\",\n      \"method\": \"Molecular docking, biolayer interferometry, immunoprecipitation, cycloheximide chase assay, OGA knockdown, cell migration/invasion assay\",\n      \"journal\": \"Open life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay (biolayer interferometry) plus substrate deglycosylation at defined site (S670), functional rescue, single lab\",\n      \"pmids\": [\"40771411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OGA suppresses O-GlcNAcylation of KLF2 at S177, reducing KLF2 protein stability; OGA knockdown promotes KLF2 O-GlcNAcylation and stability, inhibits senescence, and promotes mitophagy in dental pulp stem cells. KLF2 silencing reverses the effects of OGA knockdown.\",\n      \"method\": \"Immunoprecipitation, western blotting for O-GlcNAc on KLF2, OGA and KLF2 knockdown, senescence-associated β-galactosidase staining, mitophagy assay\",\n      \"journal\": \"BMC oral health\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-IP-based substrate identification, functional assay without in vitro reconstitution\",\n      \"pmids\": [\"40251583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OGA inhibitors (ceperognastat, ASN90, MK8719) produce convergent acute synaptotoxic effects in mouse hippocampal slices: suppression of paired-pulse facilitation/depression and long-term potentiation, increased PSD-95, reduced Synaptophysin 1, and a biphasic shift in tau phosphorylation, suggesting a class-wide mechanism of synaptic impairment from OGA inhibition.\",\n      \"method\": \"Ex vivo hippocampal slice electrophysiology (LTP, paired-pulse), immunohistochemistry for synaptic proteins and tau phosphorylation\",\n      \"journal\": \"bioRxiv / The journal of prevention of Alzheimer's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three structurally distinct inhibitors producing convergent electrophysiological phenotypes with molecular marker validation, two independent publications (preprint and peer-reviewed)\",\n      \"pmids\": [\"40654706\", \"41478829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"O-GlcNAc abundance depends on temperature across multiple organisms (Drosophila, zebrafish, mammalian cells). In cultured cells, the OGT/OGA protein ratio changes with temperature. Pharmacological OGA inhibition decoupled the temperature-dependent O-GlcNAc decrease in cultured cells, and an OGA null allele in Drosophila had the same effect, demonstrating that OGA activity is a key driver of temperature-dependent O-GlcNAc reduction.\",\n      \"method\": \"OGA inhibitor treatment, OGA null allele in Drosophila, temperature manipulation, O-GlcNAc western blotting, OGT/OGA protein quantification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null allele plus pharmacological inhibition across multiple organisms and cell systems, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.07.08.660373\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"OGA (MGEA5/NCOAT) is a dimeric, multi-domain glycoside hydrolase that removes O-GlcNAc from serine/threonine residues of hundreds of nuclear and cytoplasmic proteins; its N-terminal catalytic domain recognizes substrates through a conserved peptide-binding groove beyond the GlcNAc-binding site, its C-terminal pseudo-HAT (pHAT) domain forms a regulatory homodimer that allosterically modulates the active site and recruits DNA-damage repair factors (NONO, Ku70/80) for deglycosylation, and OGA itself is subject to regulation by O-GlcNAcylation (via OGT), proteasomal degradation (via UBR5 and RBM14/TRIM33 E3 ligase pathways), and transcriptional control (via CEBPα/RANBP2), while forming a mutual-inhibition complex with OGT that limits futile O-GlcNAc cycling and maintains homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OGA (MGEA5/NCOAT) is a multi-domain glycoside hydrolase that removes O-GlcNAc from serine/threonine residues of nuclear and cytoplasmic proteins, opposing the glycosyltransferase OGT to set cellular O-GlcNAc homeostasis [#3, #2]. Its N-terminal catalytic domain selects substrates not only through the GlcNAc moiety but through a conserved peptide-recognition groove that reads protein context beyond the sugar, as defined for substrates such as TAB1, FoxO1 and CREB [#3, #15]. The C-terminal pseudo-HAT (pHAT) domain forms catalytically incompetent symmetric homodimers that allosterically tune the active-site environment and serve as a protein-interaction platform [#13]; through this domain OGA is recruited to DNA-damage sites and deglycosylates the repair factors NONO and Ku70/80 to support non-homologous end joining [#4]. OGA and OGT engage in reciprocal inhibition: a flexible OGA segment occupies the OGT substrate groove and is itself O-GlcNAcylated, while OGT disrupts OGA dimerization and occludes its active site, coupling the two enzymes into a homeostatic unit [#6, #5]. OGA abundance is further controlled post-translationally by ubiquitin-dependent proteasomal degradation through the E3 ligases UBR5 and the RBM14/TRIM33 axis, and transcriptionally via the RANBP2–CEBPα pathway, with loss of OGA elevating global O-GlcNAcylation in cancer contexts [#9, #8, #10]. Through site-specific deglycosylation of diverse substrates—including PDLIM7, ZEB1, KLF2 and NEK7—OGA influences p53 signaling, epithelial-mesenchymal transition, cellular senescence and NLRP3-dependent pyroptosis [#7, #18, #19, #17]. Across organisms, OGA cycling links O-GlcNAc to nutrient and insulin-like signaling and is a principal driver of temperature-dependent changes in O-GlcNAc levels [#2, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that the MGEA5/OGA locus produces distinct protein isoforms with separate subcellular destinations, raising the question of compartment-specific function.\",\n      \"evidence\": \"Cell fractionation and genomic splice-variant mapping with antibody detection\",\n      \"pmids\": [\"11341771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the 75 kDa nuclear isoform not defined\", \"Catalytic activity of each isoform not directly compared\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Characterized OGA as bifunctional, assigning a putative histone acetyltransferase activity to its C-terminal domain and a zinc-finger motif that binds the histone H4 tail.\",\n      \"evidence\": \"In vitro binding and acetyltransferase assays with zinc-finger mutagenesis\",\n      \"pmids\": [\"16356930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of HAT activity in cells not established\", \"Later structural work reclassifies this region as a catalytically incompetent pseudo-HAT\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed O-GlcNAc cycling in the insulin-like signaling pathway by showing OGA loss reprograms nutrient storage and modifies dauer formation in C. elegans.\",\n      \"evidence\": \"oga-1 genetic knockout with daf-2 epistasis and metabolic biochemistry\",\n      \"pmids\": [\"16882729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct OGA substrates driving the metabolic phenotype not identified\", \"Mammalian generality of the insulin-signaling link not addressed here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how OGA achieves substrate selectivity, identifying a peptide-recognition groove that reads protein context beyond the GlcNAc sugar.\",\n      \"evidence\": \"Bacterial OGA crystal structure with human OGA mutagenesis and in vitro deglycosylation of TAB1/FoxO1/CREB\",\n      \"pmids\": [\"20863279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full human enzyme groove not solved here\", \"Sequence determinants of preferred substrates not enumerated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Probed the molecular requirements of OGA recognition at the sugar moiety and at adjacent phosphorylation sites, defining crosstalk constraints on de-O-GlcNAcylation.\",\n      \"evidence\": \"Chemoenzymatic glycopeptide synthesis and peptide-microarray OGA activity assays\",\n      \"pmids\": [\"30693278\", \"30725225\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single in vitro assays without in-cell validation\", \"Effect sizes of phospho-crosstalk modest and substrate-limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected OGA to genome maintenance, showing pHAT-dependent recruitment to lesions and deglycosylation of repair factors required for efficient NHEJ.\",\n      \"evidence\": \"Deletion mutants, affinity purification of NONO and Ku70/80, live-cell recruitment and NHEJ assays\",\n      \"pmids\": [\"34135314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis of pHAT-repair factor binding not resolved\", \"Whether OGA acts in other repair pathways not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified transcriptional control of OGA via the RANBP2–CEBPα axis, linking OGA downregulation to elevated O-GlcNAc and hepatocellular carcinoma malignancy.\",\n      \"evidence\": \"Co-IP, OGA promoter assays, SUMOylation assays, in vivo HCC models\",\n      \"pmids\": [\"34298689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CEBPα binding sites on the OGA promoter not mapped\", \"Generality beyond HCC unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed OGA is itself an OGT substrate and mapped the OGT TPR residues governing this modification, embedding OGA in a reciprocal modification loop.\",\n      \"evidence\": \"GlcNAc electrophilic probe assay with a 30-mutant OGT TPR screen and OGA truncations\",\n      \"pmids\": [\"33333092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of OGA O-GlcNAcylation not established\", \"Modified residues on OGA not pinpointed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided structural rationale for picomolar OGA inhibitors and used them chemoproteomically to detect endogenous OGA modifications including O-ubiquitination and N-formylation.\",\n      \"evidence\": \"X-ray structures of inhibitor-OGA complexes and chemoproteomic affinity purification\",\n      \"pmids\": [\"34985906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional roles of the detected endogenous PTMs not characterized\", \"Inhibitor selectivity across the proteome not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an RNA-level control of OGA via NAT10-mediated ac4C mRNA stabilization, with functional importance during oocyte maturation.\",\n      \"evidence\": \"NAT10 knockdown transcriptomics, RNA stability assays, OGA knockdown in oocytes\",\n      \"pmids\": [\"35937804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ac4C sites on OGA mRNA not pinpointed\", \"Mechanistic link between OGA loss and maturation arrest unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the structural basis of OGT-OGA mutual inhibition, establishing the enzyme pair as a self-limiting homeostatic unit.\",\n      \"evidence\": \"Cryo-EM of human OGT alone and the OGT-OGA complex\",\n      \"pmids\": [\"37907462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics and regulation of complex assembly in cells not defined\", \"How upstream signals tip the balance not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that ubiquitin-dependent degradation of OGA by UBR5 and by the RBM14/TRIM33 axis tunes cellular O-GlcNAc and drives cancer phenotypes.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, E3 ligase knockdown, mutagenesis, and xenograft models\",\n      \"pmids\": [\"38755129\", \"38678556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination sites on OGA not mapped\", \"Relative contribution of each E3 pathway in normal tissue unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed a cancer-derived stalk-domain mutation reshapes OGA's interactome and substrate preference, with deglycosylated PDLIM7 suppressing p53 and enhancing motility.\",\n      \"evidence\": \"Quantitative interactome/substrate proteomics, mutant expression, co-IP, and motility assays\",\n      \"pmids\": [\"38838015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Frequency and significance of the mutation in patient tumors not quantified\", \"Structural basis for altered +2-proline preference not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified additional site-specific OGA substrates (NEK7 T170/T172, ZEB1 S670, KLF2 S177) coupling deglycosylation to pyroptosis, EMT, and senescence in distinct disease models.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis, knockdown rescue, and in vivo/cellular functional assays\",\n      \"pmids\": [\"41066511\", \"40771411\", \"40251583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro reconstitution of direct deglycosylation lacking for several substrates\", \"KLF2 finding is Low-confidence and single-lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the multi-domain architecture, showing the pHAT domain forms symmetric homodimers that allosterically shape the active site via a conformational change.\",\n      \"evidence\": \"X-ray crystallography of the pHAT domain and cryo-EM of multi-domain OGA with SPR/SAXS (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.10.642372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Ligand or partner occupying the exposed pHAT peptide site not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked OGA activity to neuronal physiology and environmental sensing, implicating it in synaptic maturation, inhibitor-induced synaptotoxicity, and temperature-dependent O-GlcNAc dynamics.\",\n      \"evidence\": \"Hippocampal slice electrophysiology with structurally distinct inhibitors, spine morphology assays, and OGA null/inhibition across organisms\",\n      \"pmids\": [\"40654706\", \"41478829\", \"bio_10.1101_2025.08.15.670533\", \"bio_10.1101_2025.07.08.660373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrates mediating synaptic and temperature effects not identified\", \"Some findings are preprints or Low-confidence morphology-based readouts\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OGA substrate selection, dimerization state, and OGT-coupling are dynamically integrated to direct deglycosylation toward specific targets in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking pHAT dimerization, OGT inhibition, and substrate choice in cells\", \"Physiological triggers that redistribute OGA among compartments and partners undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [3, 15, 7, 18, 17]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 9, 10]}\n    ],\n    \"complexes\": [\n      \"OGT-OGA mutual-inhibition complex\",\n      \"OGA pseudo-HAT homodimer\"\n    ],\n    \"partners\": [\n      \"OGT\",\n      \"NONO\",\n      \"Ku70/80\",\n      \"UBR5\",\n      \"RBM14\",\n      \"TRIM33\",\n      \"NEK7\",\n      \"PDLIM7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":7,"faith_pct":71.42857142857143}}