{"gene":"OGT","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2014,"finding":"OGT mediates O-GlcNAcylation of the SNARE protein SNAP-29; OGT knockdown or mutation of O-GlcNAc sites in SNAP-29 promotes formation of a SNAP-29-containing SNARE complex, increases autophagosome-endosome/lysosome fusion, and promotes autophagic flux in mammalian cells and C. elegans.","method":"OGT knockdown, site-directed mutagenesis of O-GlcNAc sites in SNAP-29, autophagic flux assays, genetic depletion of ogt-1 in C. elegans","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and biochemical evidence across two organisms (mammalian cells and C. elegans), multiple orthogonal methods including mutagenesis and functional flux assays","pmids":["25419848"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures reveal that human OGT forms a functionally important scissor-shaped dimer, and within the OGT-OGA complex, a long flexible OGA segment occupies OGT's extended substrate-binding groove and positions a serine for O-GlcNAcylation, while OGT simultaneously disrupts the functional dimerization of OGA and occludes its active site—establishing mutual inhibition between OGT and OGA as a mechanism maintaining O-GlcNAc homeostasis.","method":"Cryo-electron microscopy structure determination of human OGT alone and in complex with OGA","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with functional interpretation, single study with high-resolution structural data","pmids":["37907462"],"is_preprint":false},{"year":2021,"finding":"OGT's glycosyltransferase activity is required for mammalian cell proliferation, but its protease activity (HCF-1 cleavage) is dispensable for viability; additionally, OGT has an essential noncatalytic role sufficient to rescue cell growth when catalytically inactive OGT is added back to OGT-depleted cells. Noncatalytic OGT functions especially impact proteins involved in oxidative phosphorylation and the actin cytoskeleton.","method":"Genetic complementation with separation-of-function OGT variants; auxin-inducible degron to deplete endogenous OGT; quantitative proteomics","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — separation-of-function genetic complementation with multiple variant constructs plus quantitative proteomics in a single rigorous study","pmids":["33419956"],"is_preprint":false},{"year":2023,"finding":"USP8 stabilizes OGT protein by inhibiting K48-specific poly-ubiquitination of OGT at the K117 site; STE20-like kinase (SLK)-mediated S716 phosphorylation of USP8 is required for its interaction with OGT. OGT in turn O-GlcNAcylates SLC7A11 at Ser26, which is required for SLC7A11-mediated cystine import.","method":"Co-immunoprecipitation, ubiquitination assays, mutagenesis (K117, S716), OGT depletion/overexpression, in vivo xenograft and metastasis models, intracellular cystine/GSH measurements","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, site-specific mutagenesis, and functional assays in a single lab study","pmids":["37867237"],"is_preprint":false},{"year":2019,"finding":"OGT O-GlcNAcylates RIPK3, which is associated with reduced RIPK3 protein stability; liver-specific OGT knockout leads to elevated RIPK3 and MLKL expression, excessive hepatocyte necroptosis, and progression to liver fibrosis.","method":"Liver-specific OGT knockout mice, immunoblotting for RIPK3 and MLKL, O-GlcNAcylation assays, histology","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular phenotype, association of OGT-dependent glycosylation with RIPK3 stability, single lab","pmids":["31672932"],"is_preprint":false},{"year":2020,"finding":"OGT inhibits macrophage proinflammatory activation by catalyzing O-GlcNAcylation of S6K1 (ribosomal protein S6 kinase beta-1), which suppresses S6K1 phosphorylation and downstream mTORC1 signaling.","method":"OGT knockout in macrophages, S6K1 O-GlcNAcylation assays, phosphorylation assays, high-fat diet mouse model, adipose tissue inflammation and insulin resistance measurements","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined molecular mechanism (O-GlcNAcylation of S6K1 blocking its phosphorylation), in vivo and in vitro evidence from single lab","pmids":["32601203"],"is_preprint":false},{"year":2023,"finding":"OGT controls mammalian cell viability through suppression of proteasome activity; in the absence of OGT, increased proteasome activity raises steady-state amino acid levels, driving mTOR lysosomal translocation and hyperactivation, increased oxidative phosphorylation, and ultimately mitochondrial dysfunction that blocks cell proliferation.","method":"Genome-wide CRISPR-Cas9 screen in mouse embryonic stem cells, phospho-proteomics, mTOR activity assays, mitochondrial function assays, validation in CD8+ T cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — genome-wide screen plus independent phospho-proteomic confirmation, mechanistic pathway placement with multiple orthogonal assays in a single rigorous study","pmids":["36626549"],"is_preprint":false},{"year":2017,"finding":"OGT is enriched in the postsynaptic density of excitatory synapses; OGT knockout in postsynaptic neurons decreases synaptic expression of GluA2 and GluA3 AMPA receptor subunits (but not GluA1), reduces the number of opposed excitatory presynaptic terminals, and results in fewer and less mature dendritic spines.","method":"Postsynaptic density fractionation, neuron-specific OGT knockout, immunostaining of AMPA receptor subunits, spine morphology analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular fractionation showing OGT enrichment in PSD, conditional KO with defined molecular and structural synaptic phenotypes, single lab","pmids":["28143929"],"is_preprint":false},{"year":2023,"finding":"In astrocytes of the medial prefrontal cortex, OGT modulates glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1); astrocyte-specific OGT knockout produces antidepressant-like effects and preserves neuronal morphology and Ca2+ activity deficits caused by chronic stress.","method":"Astrocyte-specific OGT knockout mice, chronic social-defeat stress model, Ca2+ imaging, O-GlcNAcylation assays for GLT-1, behavioral assays","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined substrate (GLT-1 O-GlcNAcylation) and functional behavioral/physiological readouts, single lab","pmids":["36757814"],"is_preprint":false},{"year":2016,"finding":"SC-specific OGT deletion causes tomaculous demyelinating neuropathy with progressive demyelination and axonal loss; Periaxin (PRX) is an O-GlcNAcylated myelin protein that is mislocalized within the myelin sheath when O-GlcNAcylation is absent, and phenotypes of OGT-SCKO mice closely resemble those of PRX-deficient mice.","method":"Schwann cell-specific OGT knockout mice, mass spectrometry-based proteomic identification of O-GlcNAcylated proteins in sciatic nerve, PRX localization by immunofluorescence, electrophysiology","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular substrate (PRX O-GlcNAcylation) and phenotypic readout including MS proteomics, single lab","pmids":["27629714"],"is_preprint":false},{"year":2017,"finding":"Sensory neuron-specific OGT knockout in mice results in progressive loss of epidermal nerve fiber endings and dorsal root ganglion cell body loss, beginning postnatally; nerve-ending loss precedes cell body loss, indicating axonal dieback progressing to neuronal death. Adult-inducible OGT knockout produces a similar neuropathy.","method":"Sensory neuron-specific and inducible OGT knockout mice, epidermal innervation quantification, behavioral hyposensitivity assays, axon outgrowth assays in cultured neurons","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional and inducible KO with quantitative neuropathological readouts, single lab with replicated inducible model","pmids":["28115479"],"is_preprint":false},{"year":2013,"finding":"TET3 physically interacts with OGT via its C-terminal H domain; TET3 is O-GlcNAcylated by OGT (though this does not affect global 5mC hydroxylation by TET3); TET3 interaction enhances OGT localization to chromatin by stabilizing OGT protein.","method":"Affinity purification/mass spectrometry of FLAG-TET3, Co-IP with deletion mutants, chromatin fractionation, O-GlcNAcylation assays","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with deletion mapping, MS identification of interaction, chromatin fractionation; single lab with multiple orthogonal methods","pmids":["24304661"],"is_preprint":false},{"year":2015,"finding":"OGT cleavage of HCF-1 at HCF-1PRO repeats is promoted by distinct OGT-binding sites: the glutamate at the cleavage site specifically inhibits OGT association (and UDP-GlcNAc cofactor binding), and a novel OGT-binding sequence near the first HCF-1PRO repeat enhances cleavage efficiency.","method":"Mutagenesis of HCF-1PRO repeat cleavage sites, OGT binding assays, protease activity assays, identification of novel OGT-binding sequence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — site-directed mutagenesis combined with binding and protease activity assays characterizing mechanistic determinants, single lab","pmids":["26305326"],"is_preprint":false},{"year":2018,"finding":"OGT O-GlcNAcylates c-Myc at serine 415, increasing c-Myc stability; stabilized c-Myc transcriptionally upregulates PDK2 expression, which phosphorylates pyruvate dehydrogenase to inhibit mitochondrial pyruvate metabolism, suppress ROS, and promote colorectal tumor growth.","method":"OGT depletion/overexpression in colorectal cancer cells, site-directed mutagenesis of c-Myc S415, ChIP assay, metabolic flux measurements, xenograft tumor growth assay, clinical tissue correlation","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis combined with metabolic assays and in vivo xenograft model, single lab","pmids":["38778217"],"is_preprint":false},{"year":2020,"finding":"OGT O-GlcNAcylates eNOS at Ser-615, resulting in reduced eNOS dimerization and reduced eNOS activity; this Ser-615 modification controls Ser-1177 phosphorylation, establishing a regulatory mechanism of eNOS function under glucose dysregulation.","method":"Mass spectrometry identification of O-GlcNAc site on eNOS, mutagenesis of Ser-615, eNOS dimerization assays, activity assays, patient-derived IPAH samples","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS site identification, mutagenesis, and functional eNOS assays; single lab","pmids":["32863226"],"is_preprint":false},{"year":2020,"finding":"O-GlcNAcylation of SMAD4 at Thr63 (catalyzed by OGT) inhibits interaction between SMAD4 and GSK-3β, thereby preventing GSK-3β-mediated proteasomal degradation and prolonging SMAD4 half-life; loss of this O-GlcNAcylation attenuates TGF-β/SMAD transcriptional reporter activity.","method":"Site-directed mutagenesis of SMAD4 Thr63, co-immunoprecipitation with GSK-3β, protein half-life assays, luciferase SMAD-binding-element reporter assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus Co-IP and reporter assays defining mechanism; single lab","pmids":["33199824"],"is_preprint":false},{"year":2018,"finding":"A crystal structure of human OGT with a thio-linked UDP-peptide bisubstrate inhibitor reveals how the inhibitor mimics the pseudo-Michaelis complex; modular S-linked UDP-peptide conjugates inhibit OGT activity in HeLa cell lysates (Ki = 1.3 μM for the best compound).","method":"Crystal structure determination of hOGT-inhibitor complex; in vitro OGT inhibition assays with Ki measurement; fluorescence polarimetry assay","journal":"Bioconjugate chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of OGT with inhibitor plus quantitative in vitro inhibition assay; single study with structural and biochemical validation","pmids":["29723473"],"is_preprint":false},{"year":2021,"finding":"OGT regulates β-cell mitochondrial morphology and bioenergetics through the transcription factor Pdx1; constitutive (but not inducible) β-cell OGT deletion causes swollen mitochondria, reduced glucose-stimulated oxygen consumption, and reduced ATP production; Pdx1 overexpression rescues mitochondrial dysfunction in βOGTKO islets.","method":"β-cell-specific constitutive and inducible OGT knockout mice, mitochondrial morphology imaging, Seahorse metabolic flux analysis, islet proteomics, Pdx1 overexpression rescue","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two complementary conditional KO models, functional mitochondrial assays, and genetic rescue with Pdx1; single lab","pmids":["34462257"],"is_preprint":false},{"year":2021,"finding":"O-GlcNAcylation of PARG (ADP-ribose glycohydrolase) at Ser26 by OGT promotes PARG nuclear localization and chromatin association; upon DNA damage, O-GlcNAcylated PARG is recruited to damage sites and interacts with PCNA, enhancing poly(ADP-ribosyl)ation of DDB1, attenuating DDB1 auto-ubiquitination, and thereby stabilizing DDB1.","method":"O-GlcNAcylation site mapping by MS, mutagenesis of Ser26, subcellular fractionation, Co-IP with PCNA, PAR assays, ubiquitination assays, xenograft mouse models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis combined with multiple biochemical assays and in vivo validation; single lab","pmids":["37858678"],"is_preprint":false},{"year":2021,"finding":"OGT O-GlcNAcylates KAT5 (TIP60), increasing KAT5 stability by suppressing its ubiquitination; O-GlcNAcylated KAT5 epigenetically activates TWIST1 expression via histone H4 acetylation and enhances MMP9/MMP14 expression via c-Myc acetylation, promoting EMT and HCC metastasis.","method":"PCK1 knockout hepatoma cells, KAT5 ubiquitination and stability assays, ChIP for histone H4 acetylation at TWIST1 promoter, c-Myc acetylation assays, loss-of-function and gain-of-function in vivo metastasis models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (ubiquitination, ChIP, acetylation) with in vivo validation; single lab","pmids":["34650217"],"is_preprint":false},{"year":2018,"finding":"OGT interacts with progesterone receptor (PR) and catalyzes O-GlcNAcylation of PR; O-GlcNAcylated PR is more transcriptionally active on PR-target genes despite decreased PR mRNA and total protein levels when O-GlcNAc levels are globally high.","method":"Co-immunoprecipitation of PR and OGT, O-GlcNAcylation assays of PR, transcriptional reporter assays on PR-target genes, OGT inhibitor and overexpression studies","journal":"Hormones & cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and reporter assay with partial mechanistic follow-up; single lab","pmids":["28929346"],"is_preprint":false},{"year":2021,"finding":"α-cell-specific OGT knockout mice (constitutive and inducible) show significantly reduced glucagon levels, lower α-cell glucagon content, impaired pyruvate-stimulated gluconeogenesis, and reduced in vitro glucagon secretion, demonstrating that OGT is required for α-cell function and glucagon secretion.","method":"Constitutive and inducible α-cell-specific OGT knockout mice, immunoblotting, immunofluorescence, metabolic phenotyping, in vitro glucagon secretion assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent conditional KO models with convergent functional readouts; single lab","pmids":["33460647"],"is_preprint":false},{"year":2020,"finding":"SIRT1 deacetylates CREB and inhibits its phosphorylation at Ser133; inactivated CREB suppresses OGT expression, thereby decreasing O-GlcNAcylation of tau and increasing tau phosphorylation at specific sites.","method":"SIRT1 overexpression/knockdown, CREB phosphorylation assays, OGT promoter activity, tau O-GlcNAcylation and phosphorylation measurements","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-lab study with indirect pathway placement via CREB, limited mechanistic depth in abstract","pmids":["32310828"],"is_preprint":false},{"year":2018,"finding":"OGT selectively O-GlcNAcylates lamin A (but not lamin C, lamin B1, or progerin/Δ50) at 11 sites in a 'sweet spot' unique to lamin A; residues deleted in Hutchinson-Gilford progeria (progerin Δ50) are required for substrate recognition/modification by OGT in vitro, and deletion Δ35 removes potential OGT-association motifs (residues 622–625 and 639–645).","method":"In vitro OGT glycosylation assay with purified recombinant lamin tails, mass spectrometry site mapping, deletion mutagenesis, detection in Huh7 cells and mouse liver","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with purified OGT and substrates plus MS site mapping, multiple deletion mutants tested; single lab","pmids":["29772801"],"is_preprint":false},{"year":2021,"finding":"OGT1-catalyzed O-GlcNAcylation of AKT1 enhances AKT1 protein stability and promotes its binding with FOXO1; O-GlcNAcylated AKT1 promotes FOXO1 phosphorylation at Ser238, preventing FOXO1 nuclear entry and reducing gabarapl1 promoter activity, thereby inhibiting glycophagy.","method":"OGT1 knockdown, AKT1 stability assays, Co-IP of AKT1 and FOXO1, dual-luciferase reporter assay, ChIP at gabarapl1 promoter, 13C-labeled LC-MS metabolite analysis, high-carbohydrate diet fish model","journal":"The Journal of nutritional biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — multiple methods but primarily in a non-standard vertebrate model (fish); limited mechanistic validation of OGT1 as the canonical human OGT","pmids":["36990368"],"is_preprint":false},{"year":2022,"finding":"Thermal proteome profiling reveals that O-GlcNAc bidirectionally regulates protein thermostability: 72 proteins display O-GlcNAc-dependent changes in stability, with the majority of O-GlcNAc-influenced proteins being destabilized rather than stabilized by the modification; destabilized proteins cluster into distinct macromolecular complexes.","method":"Thermal proteome profiling (TPP) comparing OGA inhibitor-treated vs. control cells, orthogonal validation of specific proteins","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteome-wide thermal shift assay with orthogonal validation; single lab, novel global mechanistic insight","pmids":["35230102"],"is_preprint":false},{"year":2021,"finding":"OGT O-GlcNAcylation of MTA1 at Ser237/241/246 in adriamycin-adaptive breast cancer cells promotes MTA1 interaction with chromatin and its association with the NuRD complex, altering genome-wide binding to gene promoters and transcriptional regulation of genotoxic stress adaptation genes.","method":"Quantitative proteomics, ChIP-seq, transcriptome analysis, mutagenesis of MTA1 O-GlcNAc sites, Co-IP with NuRD complex components","journal":"Biochimica et biophysica acta. General subjects","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS site identification, ChIP-seq, and mutagenesis with functional gene expression readouts; single lab","pmids":["34019948"],"is_preprint":false}],"current_model":"OGT is an essential mammalian enzyme that transfers a single O-GlcNAc moiety from UDP-GlcNAc onto serine/threonine residues of thousands of nuclear, cytoplasmic, and mitochondrial proteins, forming a scissor-shaped homodimer (cryo-EM structure) whose active site is mutually inhibited by OGA binding; beyond glycosylation, OGT proteolytically cleaves HCF-1 in the same active site and possesses an essential noncatalytic scaffolding function required for cell proliferation. OGT activity is regulated by USP8-mediated deubiquitination (protecting K117 from K48-linked degradation) and is transcriptionally controlled downstream of SIRT1-CREB signaling; OGT suppresses mTOR hyperactivation via proteasome inhibition, glycosylates and stabilizes substrates including c-Myc, SMAD4, RIPK3, S6K1, KAT5, and SNAP-29 to regulate autophagy, necroptosis, inflammation, and cancer metabolism, and modulates synaptic function, myelin integrity, and sensory neuron survival through tissue-specific substrate O-GlcNAcylation."},"narrative":{"mechanistic_narrative":"OGT is an essential glycosyltransferase that installs O-GlcNAc on serine/threonine residues of nuclear and cytoplasmic substrates to control protein stability, localization, and signaling across diverse cellular processes [PMID:33419956, PMID:35230102]. Cryo-EM and crystallographic studies define OGT as a scissor-shaped dimer whose extended substrate-binding groove accommodates peptide substrates, and within the OGT–OGA complex a flexible OGA segment occupies this groove while OGT occludes the OGA active site, establishing reciprocal inhibition that maintains O-GlcNAc homeostasis [PMID:37907462, PMID:29723473]. Beyond glycosylation, OGT's glycosyltransferase activity is required for mammalian cell proliferation while its HCF-1 protease activity is dispensable, and a noncatalytic scaffolding function — impacting oxidative phosphorylation and actin cytoskeleton proteins — is itself sufficient to sustain cell growth [PMID:33419956, PMID:26305326]. A recurring mechanistic theme is that OGT-catalyzed O-GlcNAcylation alters substrate fate: it stabilizes c-Myc (Ser415), SMAD4 (Thr63, by blocking GSK-3β-mediated degradation), and KAT5/TIP60 to drive cancer metabolism, TGF-β signaling, and metastasis, destabilizes RIPK3 to restrain necroptosis, and tunes enzyme activity such as eNOS dimerization and SLC7A11-mediated cystine import [PMID:38778217, PMID:33199824, PMID:34650217, PMID:31672932, PMID:32863226, PMID:37867237]; globally, O-GlcNAc bidirectionally regulates protein thermostability, more often destabilizing than stabilizing its targets [PMID:35230102]. OGT also suppresses mTOR hyperactivation by restraining proteasome activity, and dampens macrophage proinflammatory signaling by O-GlcNAcylating S6K1 to block its phosphorylation [PMID:36626549, PMID:32601203]. Tissue-specific OGT loss produces distinct phenotypes — demyelinating neuropathy through mislocalized Periaxin, sensory neuron dieback, synaptic AMPA receptor and dendritic spine defects, astrocytic regulation of glutamate transport, and impaired pancreatic α- and β-cell function — reflecting substrate-specific roles in neural and metabolic tissues [PMID:27629714, PMID:28115479, PMID:28143929, PMID:36757814, PMID:33460647, PMID:34462257].","teleology":[{"year":2013,"claim":"Established a chromatin-targeting mechanism for OGT by showing it is recruited and stabilized through a direct protein partner, addressing how a promiscuous enzyme gains spatial specificity.","evidence":"Affinity purification/MS, Co-IP with TET3 deletion mutants, and chromatin fractionation","pmids":["24304661"],"confidence":"Medium","gaps":["TET3 O-GlcNAcylation had no effect on TET3 5mC hydroxylation, leaving the functional consequence of the modification unclear","whether other partners recruit OGT to chromatin not addressed"]},{"year":2014,"claim":"Showed OGT regulates autophagy through SNARE glycosylation, linking nutrient-sensing O-GlcNAc to membrane fusion.","evidence":"OGT knockdown, SNAP-29 O-GlcNAc site mutagenesis, and autophagic flux assays in mammalian cells and C. elegans","pmids":["25419848"],"confidence":"High","gaps":["does not resolve how nutrient state quantitatively controls SNAP-29 modification stoichiometry","structural basis of glycosylation impairing SNARE assembly not defined"]},{"year":2015,"claim":"Defined the sequence determinants in HCF-1 that govern OGT's proteolytic versus glycosyltransferase outcomes within the same active site.","evidence":"Mutagenesis of HCF-1PRO cleavage sites with OGT binding and protease activity assays","pmids":["26305326"],"confidence":"Medium","gaps":["does not establish the physiological consequence of HCF-1 cleavage","single-lab biochemical characterization"]},{"year":2016,"claim":"Identified a substrate-specific role for OGT in myelin maintenance by linking Periaxin O-GlcNAcylation to its correct localization.","evidence":"Schwann cell-specific OGT knockout, MS proteomics of sciatic nerve, PRX immunofluorescence, and electrophysiology","pmids":["27629714"],"confidence":"Medium","gaps":["does not prove PRX glycosylation alone accounts for the full neuropathy","site of PRX O-GlcNAcylation and its direct effect on localization not mapped"]},{"year":2017,"claim":"Localized OGT to the postsynaptic density and demonstrated it is required for excitatory synapse composition and dendritic spine maturation, and separately that sensory neurons depend on OGT for survival.","evidence":"PSD fractionation, neuron- and sensory-neuron-specific OGT knockout, AMPA subunit immunostaining, spine and innervation quantification","pmids":["28143929","28115479"],"confidence":"Medium","gaps":["specific synaptic substrates of OGT not identified","molecular cause of axonal dieback preceding cell death not defined"]},{"year":2018,"claim":"Extended OGT's role to substrate stabilization in cancer and to substrate-recognition specificity, showing it glycosylates c-Myc (S415) to drive tumor metabolism and selectively recognizes a lamin A 'sweet spot.'","evidence":"Site-directed mutagenesis, ChIP, metabolic flux, xenografts; in vitro glycosylation of recombinant lamin tails with MS site mapping","pmids":["38778217","29772801"],"confidence":"Medium","gaps":["determinants of OGT substrate selectivity remain largely empirical","lamin A glycosylation's nuclear function not established"]},{"year":2019,"claim":"Linked OGT to control of programmed necrosis by showing RIPK3 O-GlcNAcylation reduces its stability and restrains hepatocyte necroptosis.","evidence":"Liver-specific OGT knockout mice, RIPK3/MLKL immunoblotting, O-GlcNAcylation assays, histology","pmids":["31672932"],"confidence":"Medium","gaps":["RIPK3 O-GlcNAc site not defined","mechanism connecting glycosylation to degradation not resolved"]},{"year":2020,"claim":"Demonstrated OGT acts as a brake on inflammatory and signaling pathways via substrate modifications affecting phosphorylation, glycosylation of S6K1 suppressing mTORC1 and of eNOS controlling its dimerization and activity.","evidence":"Macrophage and tissue OGT knockouts, S6K1 and eNOS O-GlcNAc/phospho assays, dimerization and activity assays, mouse models","pmids":["32601203","32863226"],"confidence":"Medium","gaps":["crosstalk between O-GlcNAc and phosphorylation sites mechanistically incomplete","SIRT1-CREB control of OGT expression (Low confidence) not independently confirmed"]},{"year":2021,"claim":"Resolved the essentiality logic of OGT by separating its glycosyltransferase, protease, and noncatalytic functions, and broadened its substrate network across DNA repair, metastasis, and pancreatic endocrine function.","evidence":"Separation-of-function complementation with degron depletion and proteomics; plus mutagenesis/Co-IP/ChIP studies on PARG, KAT5, MTA1, and conditional α/β-cell knockouts","pmids":["33419956","37858678","34650217","34019948","33460647","34462257"],"confidence":"High","gaps":["molecular identity of the noncatalytic scaffolding activity not defined","how OGT coordinates so many substrates within one tissue unresolved"]},{"year":2022,"claim":"Provided a proteome-wide view showing O-GlcNAc bidirectionally tunes protein thermostability, reframing the modification as a broad regulator of complex assembly rather than uniformly stabilizing.","evidence":"Thermal proteome profiling comparing OGA-inhibitor-treated and control cells with orthogonal validation","pmids":["35230102"],"confidence":"Medium","gaps":["whether stability changes are direct or secondary not always resolved","OGA inhibition reflects global O-GlcNAc, not OGT activity per se"]},{"year":2023,"claim":"Defined the structural basis of O-GlcNAc homeostasis through mutual OGT–OGA inhibition and placed OGT mechanistically upstream of mTOR via proteasome suppression.","evidence":"Cryo-EM of OGT alone and OGT–OGA complex; genome-wide CRISPR screen, phospho-proteomics, and mTOR/mitochondrial assays; USP8 deubiquitination of OGT","pmids":["37907462","36626549","37867237"],"confidence":"High","gaps":["how the OGT–OGA setpoint is tuned in cells not established","link between proteasome suppression and the noncatalytic essential function unresolved"]},{"year":null,"claim":"The molecular basis of OGT's essential noncatalytic scaffolding function and the general rules governing its selection among thousands of substrates remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["no defined structural/biochemical mechanism for the noncatalytic essential role","no predictive substrate-recognition code beyond the dimer groove","tissue-specific substrate prioritization not explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,13,15,23]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12,2]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,25,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18]}],"complexes":[],"partners":["OGA","TET3","HCF-1","USP8","GSK-3B","PCNA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15294","full_name":"UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit","aliases":["O-GlcNAc transferase subunit p110","O-linked N-acetylglucosamine transferase 110 kDa subunit","OGT"],"length_aa":1046,"mass_kda":116.9,"function":"Catalyzes the transfer of a single N-acetylglucosamine from UDP-GlcNAc to a serine or threonine residue in cytoplasmic and nuclear proteins resulting in their modification with a beta-linked N-acetylglucosamine (O-GlcNAc) (PubMed:12150998, PubMed:15361863, PubMed:19451179, PubMed:20018868, PubMed:21240259, PubMed:21285374, PubMed:23103939, PubMed:26237509, PubMed:26369908, PubMed:26678539, PubMed:27713473, PubMed:37541260, PubMed:37962578). Glycosylates a large and diverse number of proteins including histone H2B, AKT1, AMPK, ATG4B, CAPRIN1, EZH2, FNIP1, GSDMD, KRT7, LMNA, LMNB1, LMNB2, RPTOR, HOXA1, PFKL, KMT2E/MLL5, MAPT/TAU, TET2, RBL2, RET, NOD2 and HCFC1 (PubMed:19451179, PubMed:20200153, PubMed:21285374, PubMed:22923583, PubMed:23353889, PubMed:24474760, PubMed:26237509, PubMed:26369908, PubMed:26678539, PubMed:27527864, PubMed:30699359, PubMed:34074792, PubMed:34667079, PubMed:37541260, PubMed:37962578). Can regulate their cellular processes via cross-talk between glycosylation and phosphorylation or by affecting proteolytic processing (PubMed:21285374). Involved in insulin resistance in muscle and adipocyte cells via glycosylating insulin signaling components and inhibiting the 'Thr-308' phosphorylation of AKT1, enhancing IRS1 phosphorylation and attenuating insulin signaling (By similarity). Involved in glycolysis regulation by mediating glycosylation of 6-phosphofructokinase PFKL, inhibiting its activity (PubMed:22923583). Plays a key role in chromatin structure by mediating O-GlcNAcylation of 'Ser-112' of histone H2B: recruited to CpG-rich transcription start sites of active genes via its interaction with TET proteins (TET1, TET2 or TET3) (PubMed:22121020, PubMed:23353889). As part of the NSL complex indirectly involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). O-GlcNAcylation of 'Ser-75' of EZH2 increases its stability, and facilitating the formation of H3K27me3 by the PRC2/EED-EZH2 complex (PubMed:24474760). Stabilizes KMT2E/MLL5 by mediating its glycosylation, thereby preventing KMT2E/MLL5 ubiquitination (PubMed:26678539). Regulates circadian oscillation of the clock genes and glucose homeostasis in the liver (By similarity). Stabilizes clock proteins BMAL1 and CLOCK through O-glycosylation, which prevents their ubiquitination and subsequent degradation (By similarity). Promotes the CLOCK-BMAL1-mediated transcription of genes in the negative loop of the circadian clock such as PER1/2 and CRY1/2. O-glycosylates HCFC1 and regulates its proteolytic processing and transcriptional activity (PubMed:21285374, PubMed:28302723, PubMed:28584052). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1 (PubMed:20200153). Regulates mitochondrial motility in neurons by mediating glycosylation of TRAK1 (By similarity). Promotes autophagy by mediating O-glycosylation of ATG4B (PubMed:27527864). Acts as a regulator of mTORC1 signaling by mediating O-glycosylation of RPTOR and FNIP1: O-GlcNAcylation of RPTOR in response to glucose sufficiency promotes activation of the mTORC1 complex (PubMed:30699359, PubMed:37541260) The mitochondrial isoform (mOGT) is cytotoxic and triggers apoptosis in several cell types including INS1, an insulinoma cell line Has N-acetylglucosaminyltransferase activity: glycosylates proteins, such as HNRNPU, NEUROD1, NUP62 and PDCD6IP (PubMed:31527085). Displays specific substrate selectivity compared to other isoforms (PubMed:31527085)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O15294/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/OGT","classification":"Common Essential","n_dependent_lines":1201,"n_total_lines":1208,"dependency_fraction":0.9942052980132451},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"GSK3A","stoichiometry":0.2},{"gene":"GSK3B","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"NUP214","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/OGT","total_profiled":1310},"omim":[{"mim_id":"620773","title":"PROLINE- AND SERINE-RICH PROTEIN 1; PROSER1","url":"https://www.omim.org/entry/620773"},{"mim_id":"617742","title":"KAT8 REGULATORY NSL COMPLEX, SUBUNIT 3; KANSL3","url":"https://www.omim.org/entry/617742"},{"mim_id":"615488","title":"KAT8 REGULATORY NSL COMPLEX, SUBUNIT 2; KANSL2","url":"https://www.omim.org/entry/615488"},{"mim_id":"612839","title":"TET METHYLCYTOSINE DIOXYGENASE 2; TET2","url":"https://www.omim.org/entry/612839"},{"mim_id":"609904","title":"HISTONE GENE CLUSTER 1, H2B HISTONE FAMILY, MEMBER A; HIST1H2BA","url":"https://www.omim.org/entry/609904"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OGT"},"hgnc":{"alias_symbol":["O-GLCNAC","HRNT1","MGC22921","FLJ23071","OGT1"],"prev_symbol":[]},"alphafold":{"accession":"O15294","domains":[{"cath_id":"3.40.50.11380","chopping":"538-706_1018-1028","consensus_level":"high","plddt":96.9487,"start":538,"end":1028},{"cath_id":"3.30.720.150","chopping":"710-759_771-833","consensus_level":"high","plddt":92.8388,"start":710,"end":833},{"cath_id":"3.40.50.2000","chopping":"839-1006","consensus_level":"high","plddt":97.4986,"start":839,"end":1006}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15294","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15294-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15294-F1-predicted_aligned_error_v6.png","plddt_mean":93.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OGT","jax_strain_url":"https://www.jax.org/strain/search?query=OGT"},"sequence":{"accession":"O15294","fasta_url":"https://rest.uniprot.org/uniprotkb/O15294.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15294/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15294"}},"corpus_meta":[{"pmid":"25825515","id":"PMC_25825515","title":"A little sugar goes a long way: the cell biology of O-GlcNAc.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25825515","citation_count":472,"is_preprint":false},{"pmid":"16317114","id":"PMC_16317114","title":"The hexosamine signaling pathway: deciphering the \"O-GlcNAc code\".","date":"2005","source":"Science's STKE : signal transduction knowledge environment","url":"https://pubmed.ncbi.nlm.nih.gov/16317114","citation_count":406,"is_preprint":false},{"pmid":"21850036","id":"PMC_21850036","title":"O-GlcNAc signalling: implications for cancer cell biology.","date":"2011","source":"Nature reviews. Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21850036","citation_count":387,"is_preprint":false},{"pmid":"16781888","id":"PMC_16781888","title":"Cell signaling, the essential role of O-GlcNAc!","date":"2006","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/16781888","citation_count":322,"is_preprint":false},{"pmid":"20466550","id":"PMC_20466550","title":"O-GlcNAc signaling: a metabolic link between diabetes and cancer?","date":"2010","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/20466550","citation_count":293,"is_preprint":false},{"pmid":"19647043","id":"PMC_19647043","title":"The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19647043","citation_count":276,"is_preprint":false},{"pmid":"23642195","id":"PMC_23642195","title":"O-GlcNAc cycling: a link between metabolism and chronic disease.","date":"2013","source":"Annual review of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/23642195","citation_count":263,"is_preprint":false},{"pmid":"25419848","id":"PMC_25419848","title":"O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation.","date":"2014","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25419848","citation_count":245,"is_preprint":false},{"pmid":"25336656","id":"PMC_25336656","title":"The emerging link between O-GlcNAc and Alzheimer disease.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25336656","citation_count":212,"is_preprint":false},{"pmid":"20202486","id":"PMC_20202486","title":"Modulation of transcription factor function by O-GlcNAc modification.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/20202486","citation_count":202,"is_preprint":false},{"pmid":"23647930","id":"PMC_23647930","title":"Cracking the O-GlcNAc code in metabolism.","date":"2013","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/23647930","citation_count":198,"is_preprint":false},{"pmid":"17940659","id":"PMC_17940659","title":"O-GlcNAc modification in diabetes and Alzheimer's disease.","date":"2007","source":"Molecular bioSystems","url":"https://pubmed.ncbi.nlm.nih.gov/17940659","citation_count":191,"is_preprint":false},{"pmid":"25336642","id":"PMC_25336642","title":"Cancer metabolism and elevated O-GlcNAc in oncogenic signaling.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25336642","citation_count":178,"is_preprint":false},{"pmid":"12615051","id":"PMC_12615051","title":"O-GlcNAc: a regulatory post-translational modification.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12615051","citation_count":159,"is_preprint":false},{"pmid":"27294441","id":"PMC_27294441","title":"The Biochemistry of O-GlcNAc Transferase: Which Functions Make It Essential in Mammalian Cells?","date":"2016","source":"Annual review of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27294441","citation_count":151,"is_preprint":false},{"pmid":"21074472","id":"PMC_21074472","title":"O-GlcNAc modification, insulin signaling and diabetic complications.","date":"2010","source":"Diabetes & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21074472","citation_count":130,"is_preprint":false},{"pmid":"20651294","id":"PMC_20651294","title":"O-GlcNAc signaling in the cardiovascular system.","date":"2010","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/20651294","citation_count":128,"is_preprint":false},{"pmid":"23836420","id":"PMC_23836420","title":"O-GlcNAc in cancer biology.","date":"2013","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/23836420","citation_count":126,"is_preprint":false},{"pmid":"23146438","id":"PMC_23146438","title":"O-GlcNAc processing enzymes: catalytic mechanisms, substrate specificity, and enzyme regulation.","date":"2012","source":"Current opinion in chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/23146438","citation_count":125,"is_preprint":false},{"pmid":"27259471","id":"PMC_27259471","title":"Roles of O-GlcNAc in chronic diseases of aging.","date":"2016","source":"Molecular aspects of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27259471","citation_count":124,"is_preprint":false},{"pmid":"19961900","id":"PMC_19961900","title":"O-GlcNAc protein modification in plants: Evolution and function.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19961900","citation_count":122,"is_preprint":false},{"pmid":"29594839","id":"PMC_29594839","title":"O-GlcNAc in cancer: An Oncometabolism-fueled vicious cycle.","date":"2018","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/29594839","citation_count":116,"is_preprint":false},{"pmid":"14568619","id":"PMC_14568619","title":"Dynamic interplay between O-GlcNAc and O-phosphate: the sweet side of protein regulation.","date":"2003","source":"Current opinion in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/14568619","citation_count":115,"is_preprint":false},{"pmid":"24287310","id":"PMC_24287310","title":"O-GlcNAc and the cardiovascular system.","date":"2013","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/24287310","citation_count":114,"is_preprint":false},{"pmid":"24769077","id":"PMC_24769077","title":"O-GlcNAc signaling in cancer metabolism and epigenetics.","date":"2014","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/24769077","citation_count":114,"is_preprint":false},{"pmid":"30464755","id":"PMC_30464755","title":"O-GlcNAc as an Integrator of Signaling Pathways.","date":"2018","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30464755","citation_count":112,"is_preprint":false},{"pmid":"18929495","id":"PMC_18929495","title":"O-GlcNAc modification of transcription factors, glucose sensing and glucotoxicity.","date":"2008","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/18929495","citation_count":105,"is_preprint":false},{"pmid":"37867237","id":"PMC_37867237","title":"Targeting USP8 Inhibits O-GlcNAcylation of SLC7A11 to Promote Ferroptosis of Hepatocellular Carcinoma via Stabilization of OGT.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37867237","citation_count":101,"is_preprint":false},{"pmid":"20488252","id":"PMC_20488252","title":"O-GlcNAc cycling: emerging roles in development and epigenetics.","date":"2010","source":"Seminars in cell & developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/20488252","citation_count":95,"is_preprint":false},{"pmid":"33916244","id":"PMC_33916244","title":"O-GlcNAcylation and O-GlcNAc Cycling Regulate Gene Transcription: Emerging Roles in Cancer.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33916244","citation_count":89,"is_preprint":false},{"pmid":"28143929","id":"PMC_28143929","title":"O-GlcNAc transferase regulates excitatory synapse maturity.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28143929","citation_count":78,"is_preprint":false},{"pmid":"24304661","id":"PMC_24304661","title":"TET3-OGT interaction increases the stability and the presence of OGT in chromatin.","date":"2013","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/24304661","citation_count":75,"is_preprint":false},{"pmid":"36757814","id":"PMC_36757814","title":"O-GlcNAc transferase in astrocytes modulates depression-related stress susceptibility through glutamatergic synaptic transmission.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/36757814","citation_count":74,"is_preprint":false},{"pmid":"25173736","id":"PMC_25173736","title":"O-GlcNAc transferase and O-GlcNAcase: achieving target substrate specificity.","date":"2014","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/25173736","citation_count":73,"is_preprint":false},{"pmid":"35302357","id":"PMC_35302357","title":"Demystifying the O-GlcNAc Code: A Systems View.","date":"2022","source":"Chemical reviews","url":"https://pubmed.ncbi.nlm.nih.gov/35302357","citation_count":71,"is_preprint":false},{"pmid":"31672932","id":"PMC_31672932","title":"O-GlcNAc transferase suppresses necroptosis and liver fibrosis.","date":"2019","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/31672932","citation_count":71,"is_preprint":false},{"pmid":"33419956","id":"PMC_33419956","title":"Mammalian cell proliferation requires noncatalytic functions of O-GlcNAc transferase.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33419956","citation_count":66,"is_preprint":false},{"pmid":"11522385","id":"PMC_11522385","title":"Nucleocytoplasmic O-glycosylation: O-GlcNAc and functional proteomics.","date":"2001","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/11522385","citation_count":65,"is_preprint":false},{"pmid":"29049853","id":"PMC_29049853","title":"Nutrient-driven O-GlcNAc in proteostasis and neurodegeneration.","date":"2017","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29049853","citation_count":64,"is_preprint":false},{"pmid":"24524620","id":"PMC_24524620","title":"Functional O-GlcNAc modifications: implications in molecular regulation and pathophysiology.","date":"2014","source":"Critical reviews in biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24524620","citation_count":63,"is_preprint":false},{"pmid":"26862193","id":"PMC_26862193","title":"O-GlcNAc transferase inhibitors: current tools and future challenges.","date":"2016","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/26862193","citation_count":61,"is_preprint":false},{"pmid":"30985105","id":"PMC_30985105","title":"O-GlcNAc Modification Protects against Protein Misfolding and Aggregation in Neurodegenerative Disease.","date":"2019","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30985105","citation_count":60,"is_preprint":false},{"pmid":"32601203","id":"PMC_32601203","title":"OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32601203","citation_count":56,"is_preprint":false},{"pmid":"25336649","id":"PMC_25336649","title":"The making of a sweet modification: structure and function of O-GlcNAc transferase.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25336649","citation_count":55,"is_preprint":false},{"pmid":"27629714","id":"PMC_27629714","title":"Schwann Cell O-GlcNAc Glycosylation Is Required for Myelin Maintenance and Axon Integrity.","date":"2016","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27629714","citation_count":54,"is_preprint":false},{"pmid":"30105004","id":"PMC_30105004","title":"O-GlcNAc: A Sweetheart of the Cell Cycle and DNA Damage Response.","date":"2018","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30105004","citation_count":52,"is_preprint":false},{"pmid":"24550151","id":"PMC_24550151","title":"The role of O-GlcNAc signaling in the pathogenesis of diabetic retinopathy.","date":"2014","source":"Proteomics. Clinical applications","url":"https://pubmed.ncbi.nlm.nih.gov/24550151","citation_count":52,"is_preprint":false},{"pmid":"34650217","id":"PMC_34650217","title":"O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34650217","citation_count":51,"is_preprint":false},{"pmid":"36359905","id":"PMC_36359905","title":"Integration of O-GlcNAc into Stress Response Pathways.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36359905","citation_count":50,"is_preprint":false},{"pmid":"29548027","id":"PMC_29548027","title":"Functional crosstalk among oxidative stress and O-GlcNAc signaling pathways.","date":"2018","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29548027","citation_count":50,"is_preprint":false},{"pmid":"28115479","id":"PMC_28115479","title":"O-GlcNAc Transferase Is Essential for Sensory Neuron Survival and Maintenance.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28115479","citation_count":49,"is_preprint":false},{"pmid":"34934185","id":"PMC_34934185","title":"Tools, tactics and objectives to interrogate cellular roles of O-GlcNAc in disease.","date":"2021","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/34934185","citation_count":48,"is_preprint":false},{"pmid":"25336650","id":"PMC_25336650","title":"O-GlcNAcase: promiscuous hexosaminidase or key regulator of O-GlcNAc signaling?","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25336650","citation_count":48,"is_preprint":false},{"pmid":"37918804","id":"PMC_37918804","title":"Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37918804","citation_count":40,"is_preprint":false},{"pmid":"34764359","id":"PMC_34764359","title":"Blocked O-GlcNAc cycling alters mitochondrial morphology, function, and mass.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34764359","citation_count":39,"is_preprint":false},{"pmid":"15944815","id":"PMC_15944815","title":"O-GlcNAc modification of nucleocytoplasmic proteins and diabetes.","date":"2005","source":"Medical molecular morphology","url":"https://pubmed.ncbi.nlm.nih.gov/15944815","citation_count":39,"is_preprint":false},{"pmid":"38778217","id":"PMC_38778217","title":"The OGT-c-Myc-PDK2 axis rewires the TCA cycle and promotes colorectal tumor growth.","date":"2024","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/38778217","citation_count":38,"is_preprint":false},{"pmid":"33535148","id":"PMC_33535148","title":"Monitoring and modulating O-GlcNAcylation: assays and inhibitors of O-GlcNAc processing enzymes.","date":"2021","source":"Current opinion in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/33535148","citation_count":37,"is_preprint":false},{"pmid":"23906602","id":"PMC_23906602","title":"Tools for probing and perturbing O-GlcNAc in cells and in vivo.","date":"2013","source":"Current opinion in chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/23906602","citation_count":37,"is_preprint":false},{"pmid":"30669087","id":"PMC_30669087","title":"Structure and function of extracellular O-GlcNAc.","date":"2019","source":"Current opinion in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/30669087","citation_count":36,"is_preprint":false},{"pmid":"32155042","id":"PMC_32155042","title":"The O-GlcNAc Modification on Kinases.","date":"2020","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/32155042","citation_count":36,"is_preprint":false},{"pmid":"28408483","id":"PMC_28408483","title":"O-GlcNAc cycling and the regulation of nucleocytoplasmic dynamics.","date":"2017","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/28408483","citation_count":35,"is_preprint":false},{"pmid":"30523150","id":"PMC_30523150","title":"O-GlcNAc homeostasis contributes to cell fate decisions during hematopoiesis.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30523150","citation_count":35,"is_preprint":false},{"pmid":"28408476","id":"PMC_28408476","title":"OGT: a short overview of an enzyme standing out from usual glycosyltransferases.","date":"2017","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/28408476","citation_count":34,"is_preprint":false},{"pmid":"35230102","id":"PMC_35230102","title":"Thermal Proteome Profiling Reveals the O-GlcNAc-Dependent Meltome.","date":"2022","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/35230102","citation_count":34,"is_preprint":false},{"pmid":"36626549","id":"PMC_36626549","title":"OGT controls mammalian cell viability by regulating the proteasome/mTOR/ mitochondrial axis.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36626549","citation_count":33,"is_preprint":false},{"pmid":"36276652","id":"PMC_36276652","title":"Specificity of oligonucleotide gene therapy (OGT) agents.","date":"2022","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/36276652","citation_count":32,"is_preprint":false},{"pmid":"35499042","id":"PMC_35499042","title":"O-GlcNAc modification mediates aquaporin 3 to coordinate endometrial cell glycolysis and affects embryo implantation.","date":"2021","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/35499042","citation_count":32,"is_preprint":false},{"pmid":"37907462","id":"PMC_37907462","title":"Cryo-EM structure of human O-GlcNAcylation enzyme pair OGT-OGA complex.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37907462","citation_count":31,"is_preprint":false},{"pmid":"29790000","id":"PMC_29790000","title":"O-GlcNAc cycling in the developing, adult and geriatric brain.","date":"2018","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/29790000","citation_count":30,"is_preprint":false},{"pmid":"32863226","id":"PMC_32863226","title":"Specific O-GlcNAc modification at Ser-615 modulates eNOS function.","date":"2020","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/32863226","citation_count":30,"is_preprint":false},{"pmid":"29723473","id":"PMC_29723473","title":"Thio-Linked UDP-Peptide Conjugates as O-GlcNAc Transferase Inhibitors.","date":"2018","source":"Bioconjugate chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29723473","citation_count":30,"is_preprint":false},{"pmid":"33472950","id":"PMC_33472950","title":"O-GlcNAc Transferase - An Auxiliary Factor or a Full-blown Oncogene?","date":"2021","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/33472950","citation_count":29,"is_preprint":false},{"pmid":"33329753","id":"PMC_33329753","title":"O-GlcNAc: Regulator of Signaling and Epigenetics Linked to X-linked Intellectual Disability.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33329753","citation_count":29,"is_preprint":false},{"pmid":"35288161","id":"PMC_35288161","title":"OGT as potential novel target: Structure, function and inhibitors.","date":"2022","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/35288161","citation_count":29,"is_preprint":false},{"pmid":"38447797","id":"PMC_38447797","title":"OGT and OGA: Sweet guardians of the genome.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38447797","citation_count":28,"is_preprint":false},{"pmid":"30952976","id":"PMC_30952976","title":"O-GlcNAc Transferase Inhibition Differentially Affects Breast Cancer Subtypes.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30952976","citation_count":28,"is_preprint":false},{"pmid":"33199824","id":"PMC_33199824","title":"O-GlcNAc stabilizes SMAD4 by inhibiting GSK-3β-mediated proteasomal degradation.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33199824","citation_count":28,"is_preprint":false},{"pmid":"32731422","id":"PMC_32731422","title":"The Emerging Role of Galectins and O-GlcNAc Homeostasis in Processes of Cellular Differentiation.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32731422","citation_count":27,"is_preprint":false},{"pmid":"32310828","id":"PMC_32310828","title":"SIRT1 regulates O-GlcNAcylation of tau through OGT.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32310828","citation_count":26,"is_preprint":false},{"pmid":"29223644","id":"PMC_29223644","title":"Functional significance of O-GlcNAc modification in regulating neuronal properties.","date":"2017","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/29223644","citation_count":25,"is_preprint":false},{"pmid":"36111295","id":"PMC_36111295","title":"A nexus of lipid and O-Glcnac metabolism in physiology and disease.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/36111295","citation_count":24,"is_preprint":false},{"pmid":"28929346","id":"PMC_28929346","title":"O-GlcNAc-Dependent Regulation of Progesterone Receptor Function in Breast Cancer.","date":"2017","source":"Hormones & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28929346","citation_count":24,"is_preprint":false},{"pmid":"34462257","id":"PMC_34462257","title":"OGT Regulates Mitochondrial Biogenesis and Function via Diabetes Susceptibility Gene Pdx1.","date":"2021","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/34462257","citation_count":24,"is_preprint":false},{"pmid":"34502531","id":"PMC_34502531","title":"OGT Protein Interaction Network (OGT-PIN): A Curated Database of Experimentally Identified Interaction Proteins of OGT.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34502531","citation_count":22,"is_preprint":false},{"pmid":"25141978","id":"PMC_25141978","title":"The potential role of O-GlcNAc modification in cancer epigenetics.","date":"2014","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/25141978","citation_count":22,"is_preprint":false},{"pmid":"26305326","id":"PMC_26305326","title":"Distinct OGT-Binding Sites Promote HCF-1 Cleavage.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26305326","citation_count":22,"is_preprint":false},{"pmid":"19874270","id":"PMC_19874270","title":"O-GlcNAc modification and the tauopathies: insights from chemical biology.","date":"2009","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/19874270","citation_count":21,"is_preprint":false},{"pmid":"29772801","id":"PMC_29772801","title":"OGT (O-GlcNAc Transferase) Selectively Modifies Multiple Residues Unique to Lamin A.","date":"2018","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/29772801","citation_count":21,"is_preprint":false},{"pmid":"37858678","id":"PMC_37858678","title":"O-GlcNAc has crosstalk with ADP-ribosylation via PARG.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37858678","citation_count":20,"is_preprint":false},{"pmid":"29204729","id":"PMC_29204729","title":"\"Nutrient-sensing\" and self-renewal: O-GlcNAc in a new role.","date":"2017","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/29204729","citation_count":20,"is_preprint":false},{"pmid":"37408229","id":"PMC_37408229","title":"O-GlcNAc Dynamics: The Sweet Side of Protein Trafficking Regulation in Mammalian Cells.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37408229","citation_count":20,"is_preprint":false},{"pmid":"36990368","id":"PMC_36990368","title":"Glycophagy mediated glucose-induced changes of hepatic glycogen metabolism via OGT1-AKT1-FOXO1Ser238 pathway.","date":"2023","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36990368","citation_count":20,"is_preprint":false},{"pmid":"30082668","id":"PMC_30082668","title":"'O-GlcNAc Code' Mediated Biological Functions of Downstream Proteins.","date":"2018","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/30082668","citation_count":20,"is_preprint":false},{"pmid":"28638491","id":"PMC_28638491","title":"O-GlcNAc-ylation in the Nuclear Pore Complex.","date":"2016","source":"Cellular and molecular bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/28638491","citation_count":20,"is_preprint":false},{"pmid":"29404877","id":"PMC_29404877","title":"O-GlcNAc: a novel regulator of immunometabolism.","date":"2018","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/29404877","citation_count":19,"is_preprint":false},{"pmid":"29904918","id":"PMC_29904918","title":"T cell development and the physiological role of O-GlcNAc.","date":"2018","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/29904918","citation_count":19,"is_preprint":false},{"pmid":"34019948","id":"PMC_34019948","title":"O-GlcNAc modification regulates MTA1 transcriptional activity during breast cancer cell genotoxic adaptation.","date":"2021","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/34019948","citation_count":19,"is_preprint":false},{"pmid":"36442303","id":"PMC_36442303","title":"O-GlcNAc transferase contributes to sex-specific placental deregulation in gestational diabetes.","date":"2022","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/36442303","citation_count":18,"is_preprint":false},{"pmid":"33460647","id":"PMC_33460647","title":"O-linked N-acetylglucosamine transferase (OGT) regulates pancreatic α-cell function in mice.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33460647","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43878,"output_tokens":7189,"usd":0.119734,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16221,"output_tokens":4156,"usd":0.092503,"stage2_stop_reason":"end_turn"},"total_usd":0.212237,"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\": 2014,\n      \"finding\": \"OGT mediates O-GlcNAcylation of the SNARE protein SNAP-29; OGT knockdown or mutation of O-GlcNAc sites in SNAP-29 promotes formation of a SNAP-29-containing SNARE complex, increases autophagosome-endosome/lysosome fusion, and promotes autophagic flux in mammalian cells and C. elegans.\",\n      \"method\": \"OGT knockdown, site-directed mutagenesis of O-GlcNAc sites in SNAP-29, autophagic flux assays, genetic depletion of ogt-1 in C. elegans\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and biochemical evidence across two organisms (mammalian cells and C. elegans), multiple orthogonal methods including mutagenesis and functional flux assays\",\n      \"pmids\": [\"25419848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures reveal that human OGT forms a functionally important scissor-shaped dimer, and within the OGT-OGA complex, a long flexible OGA segment occupies OGT's extended substrate-binding groove and positions a serine for O-GlcNAcylation, while OGT simultaneously disrupts the functional dimerization of OGA and occludes its active site—establishing mutual inhibition between OGT and OGA as a mechanism maintaining O-GlcNAc homeostasis.\",\n      \"method\": \"Cryo-electron microscopy structure determination of human OGT alone and in complex with OGA\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with functional interpretation, single study with high-resolution structural data\",\n      \"pmids\": [\"37907462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OGT's glycosyltransferase activity is required for mammalian cell proliferation, but its protease activity (HCF-1 cleavage) is dispensable for viability; additionally, OGT has an essential noncatalytic role sufficient to rescue cell growth when catalytically inactive OGT is added back to OGT-depleted cells. Noncatalytic OGT functions especially impact proteins involved in oxidative phosphorylation and the actin cytoskeleton.\",\n      \"method\": \"Genetic complementation with separation-of-function OGT variants; auxin-inducible degron to deplete endogenous OGT; quantitative proteomics\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — separation-of-function genetic complementation with multiple variant constructs plus quantitative proteomics in a single rigorous study\",\n      \"pmids\": [\"33419956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP8 stabilizes OGT protein by inhibiting K48-specific poly-ubiquitination of OGT at the K117 site; STE20-like kinase (SLK)-mediated S716 phosphorylation of USP8 is required for its interaction with OGT. OGT in turn O-GlcNAcylates SLC7A11 at Ser26, which is required for SLC7A11-mediated cystine import.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, mutagenesis (K117, S716), OGT depletion/overexpression, in vivo xenograft and metastasis models, intracellular cystine/GSH measurements\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, site-specific mutagenesis, and functional assays in a single lab study\",\n      \"pmids\": [\"37867237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OGT O-GlcNAcylates RIPK3, which is associated with reduced RIPK3 protein stability; liver-specific OGT knockout leads to elevated RIPK3 and MLKL expression, excessive hepatocyte necroptosis, and progression to liver fibrosis.\",\n      \"method\": \"Liver-specific OGT knockout mice, immunoblotting for RIPK3 and MLKL, O-GlcNAcylation assays, histology\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular phenotype, association of OGT-dependent glycosylation with RIPK3 stability, single lab\",\n      \"pmids\": [\"31672932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OGT inhibits macrophage proinflammatory activation by catalyzing O-GlcNAcylation of S6K1 (ribosomal protein S6 kinase beta-1), which suppresses S6K1 phosphorylation and downstream mTORC1 signaling.\",\n      \"method\": \"OGT knockout in macrophages, S6K1 O-GlcNAcylation assays, phosphorylation assays, high-fat diet mouse model, adipose tissue inflammation and insulin resistance measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined molecular mechanism (O-GlcNAcylation of S6K1 blocking its phosphorylation), in vivo and in vitro evidence from single lab\",\n      \"pmids\": [\"32601203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OGT controls mammalian cell viability through suppression of proteasome activity; in the absence of OGT, increased proteasome activity raises steady-state amino acid levels, driving mTOR lysosomal translocation and hyperactivation, increased oxidative phosphorylation, and ultimately mitochondrial dysfunction that blocks cell proliferation.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen in mouse embryonic stem cells, phospho-proteomics, mTOR activity assays, mitochondrial function assays, validation in CD8+ T cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — genome-wide screen plus independent phospho-proteomic confirmation, mechanistic pathway placement with multiple orthogonal assays in a single rigorous study\",\n      \"pmids\": [\"36626549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OGT is enriched in the postsynaptic density of excitatory synapses; OGT knockout in postsynaptic neurons decreases synaptic expression of GluA2 and GluA3 AMPA receptor subunits (but not GluA1), reduces the number of opposed excitatory presynaptic terminals, and results in fewer and less mature dendritic spines.\",\n      \"method\": \"Postsynaptic density fractionation, neuron-specific OGT knockout, immunostaining of AMPA receptor subunits, spine morphology analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular fractionation showing OGT enrichment in PSD, conditional KO with defined molecular and structural synaptic phenotypes, single lab\",\n      \"pmids\": [\"28143929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In astrocytes of the medial prefrontal cortex, OGT modulates glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1); astrocyte-specific OGT knockout produces antidepressant-like effects and preserves neuronal morphology and Ca2+ activity deficits caused by chronic stress.\",\n      \"method\": \"Astrocyte-specific OGT knockout mice, chronic social-defeat stress model, Ca2+ imaging, O-GlcNAcylation assays for GLT-1, behavioral assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined substrate (GLT-1 O-GlcNAcylation) and functional behavioral/physiological readouts, single lab\",\n      \"pmids\": [\"36757814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SC-specific OGT deletion causes tomaculous demyelinating neuropathy with progressive demyelination and axonal loss; Periaxin (PRX) is an O-GlcNAcylated myelin protein that is mislocalized within the myelin sheath when O-GlcNAcylation is absent, and phenotypes of OGT-SCKO mice closely resemble those of PRX-deficient mice.\",\n      \"method\": \"Schwann cell-specific OGT knockout mice, mass spectrometry-based proteomic identification of O-GlcNAcylated proteins in sciatic nerve, PRX localization by immunofluorescence, electrophysiology\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular substrate (PRX O-GlcNAcylation) and phenotypic readout including MS proteomics, single lab\",\n      \"pmids\": [\"27629714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sensory neuron-specific OGT knockout in mice results in progressive loss of epidermal nerve fiber endings and dorsal root ganglion cell body loss, beginning postnatally; nerve-ending loss precedes cell body loss, indicating axonal dieback progressing to neuronal death. Adult-inducible OGT knockout produces a similar neuropathy.\",\n      \"method\": \"Sensory neuron-specific and inducible OGT knockout mice, epidermal innervation quantification, behavioral hyposensitivity assays, axon outgrowth assays in cultured neurons\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional and inducible KO with quantitative neuropathological readouts, single lab with replicated inducible model\",\n      \"pmids\": [\"28115479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TET3 physically interacts with OGT via its C-terminal H domain; TET3 is O-GlcNAcylated by OGT (though this does not affect global 5mC hydroxylation by TET3); TET3 interaction enhances OGT localization to chromatin by stabilizing OGT protein.\",\n      \"method\": \"Affinity purification/mass spectrometry of FLAG-TET3, Co-IP with deletion mutants, chromatin fractionation, O-GlcNAcylation assays\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with deletion mapping, MS identification of interaction, chromatin fractionation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24304661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"OGT cleavage of HCF-1 at HCF-1PRO repeats is promoted by distinct OGT-binding sites: the glutamate at the cleavage site specifically inhibits OGT association (and UDP-GlcNAc cofactor binding), and a novel OGT-binding sequence near the first HCF-1PRO repeat enhances cleavage efficiency.\",\n      \"method\": \"Mutagenesis of HCF-1PRO repeat cleavage sites, OGT binding assays, protease activity assays, identification of novel OGT-binding sequence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-directed mutagenesis combined with binding and protease activity assays characterizing mechanistic determinants, single lab\",\n      \"pmids\": [\"26305326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OGT O-GlcNAcylates c-Myc at serine 415, increasing c-Myc stability; stabilized c-Myc transcriptionally upregulates PDK2 expression, which phosphorylates pyruvate dehydrogenase to inhibit mitochondrial pyruvate metabolism, suppress ROS, and promote colorectal tumor growth.\",\n      \"method\": \"OGT depletion/overexpression in colorectal cancer cells, site-directed mutagenesis of c-Myc S415, ChIP assay, metabolic flux measurements, xenograft tumor growth assay, clinical tissue correlation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis combined with metabolic assays and in vivo xenograft model, single lab\",\n      \"pmids\": [\"38778217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OGT O-GlcNAcylates eNOS at Ser-615, resulting in reduced eNOS dimerization and reduced eNOS activity; this Ser-615 modification controls Ser-1177 phosphorylation, establishing a regulatory mechanism of eNOS function under glucose dysregulation.\",\n      \"method\": \"Mass spectrometry identification of O-GlcNAc site on eNOS, mutagenesis of Ser-615, eNOS dimerization assays, activity assays, patient-derived IPAH samples\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS site identification, mutagenesis, and functional eNOS assays; single lab\",\n      \"pmids\": [\"32863226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"O-GlcNAcylation of SMAD4 at Thr63 (catalyzed by OGT) inhibits interaction between SMAD4 and GSK-3β, thereby preventing GSK-3β-mediated proteasomal degradation and prolonging SMAD4 half-life; loss of this O-GlcNAcylation attenuates TGF-β/SMAD transcriptional reporter activity.\",\n      \"method\": \"Site-directed mutagenesis of SMAD4 Thr63, co-immunoprecipitation with GSK-3β, protein half-life assays, luciferase SMAD-binding-element reporter assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus Co-IP and reporter assays defining mechanism; single lab\",\n      \"pmids\": [\"33199824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A crystal structure of human OGT with a thio-linked UDP-peptide bisubstrate inhibitor reveals how the inhibitor mimics the pseudo-Michaelis complex; modular S-linked UDP-peptide conjugates inhibit OGT activity in HeLa cell lysates (Ki = 1.3 μM for the best compound).\",\n      \"method\": \"Crystal structure determination of hOGT-inhibitor complex; in vitro OGT inhibition assays with Ki measurement; fluorescence polarimetry assay\",\n      \"journal\": \"Bioconjugate chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of OGT with inhibitor plus quantitative in vitro inhibition assay; single study with structural and biochemical validation\",\n      \"pmids\": [\"29723473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OGT regulates β-cell mitochondrial morphology and bioenergetics through the transcription factor Pdx1; constitutive (but not inducible) β-cell OGT deletion causes swollen mitochondria, reduced glucose-stimulated oxygen consumption, and reduced ATP production; Pdx1 overexpression rescues mitochondrial dysfunction in βOGTKO islets.\",\n      \"method\": \"β-cell-specific constitutive and inducible OGT knockout mice, mitochondrial morphology imaging, Seahorse metabolic flux analysis, islet proteomics, Pdx1 overexpression rescue\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary conditional KO models, functional mitochondrial assays, and genetic rescue with Pdx1; single lab\",\n      \"pmids\": [\"34462257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"O-GlcNAcylation of PARG (ADP-ribose glycohydrolase) at Ser26 by OGT promotes PARG nuclear localization and chromatin association; upon DNA damage, O-GlcNAcylated PARG is recruited to damage sites and interacts with PCNA, enhancing poly(ADP-ribosyl)ation of DDB1, attenuating DDB1 auto-ubiquitination, and thereby stabilizing DDB1.\",\n      \"method\": \"O-GlcNAcylation site mapping by MS, mutagenesis of Ser26, subcellular fractionation, Co-IP with PCNA, PAR assays, ubiquitination assays, xenograft mouse models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis combined with multiple biochemical assays and in vivo validation; single lab\",\n      \"pmids\": [\"37858678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OGT O-GlcNAcylates KAT5 (TIP60), increasing KAT5 stability by suppressing its ubiquitination; O-GlcNAcylated KAT5 epigenetically activates TWIST1 expression via histone H4 acetylation and enhances MMP9/MMP14 expression via c-Myc acetylation, promoting EMT and HCC metastasis.\",\n      \"method\": \"PCK1 knockout hepatoma cells, KAT5 ubiquitination and stability assays, ChIP for histone H4 acetylation at TWIST1 promoter, c-Myc acetylation assays, loss-of-function and gain-of-function in vivo metastasis models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (ubiquitination, ChIP, acetylation) with in vivo validation; single lab\",\n      \"pmids\": [\"34650217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OGT interacts with progesterone receptor (PR) and catalyzes O-GlcNAcylation of PR; O-GlcNAcylated PR is more transcriptionally active on PR-target genes despite decreased PR mRNA and total protein levels when O-GlcNAc levels are globally high.\",\n      \"method\": \"Co-immunoprecipitation of PR and OGT, O-GlcNAcylation assays of PR, transcriptional reporter assays on PR-target genes, OGT inhibitor and overexpression studies\",\n      \"journal\": \"Hormones & cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and reporter assay with partial mechanistic follow-up; single lab\",\n      \"pmids\": [\"28929346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"α-cell-specific OGT knockout mice (constitutive and inducible) show significantly reduced glucagon levels, lower α-cell glucagon content, impaired pyruvate-stimulated gluconeogenesis, and reduced in vitro glucagon secretion, demonstrating that OGT is required for α-cell function and glucagon secretion.\",\n      \"method\": \"Constitutive and inducible α-cell-specific OGT knockout mice, immunoblotting, immunofluorescence, metabolic phenotyping, in vitro glucagon secretion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent conditional KO models with convergent functional readouts; single lab\",\n      \"pmids\": [\"33460647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIRT1 deacetylates CREB and inhibits its phosphorylation at Ser133; inactivated CREB suppresses OGT expression, thereby decreasing O-GlcNAcylation of tau and increasing tau phosphorylation at specific sites.\",\n      \"method\": \"SIRT1 overexpression/knockdown, CREB phosphorylation assays, OGT promoter activity, tau O-GlcNAcylation and phosphorylation measurements\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab study with indirect pathway placement via CREB, limited mechanistic depth in abstract\",\n      \"pmids\": [\"32310828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OGT selectively O-GlcNAcylates lamin A (but not lamin C, lamin B1, or progerin/Δ50) at 11 sites in a 'sweet spot' unique to lamin A; residues deleted in Hutchinson-Gilford progeria (progerin Δ50) are required for substrate recognition/modification by OGT in vitro, and deletion Δ35 removes potential OGT-association motifs (residues 622–625 and 639–645).\",\n      \"method\": \"In vitro OGT glycosylation assay with purified recombinant lamin tails, mass spectrometry site mapping, deletion mutagenesis, detection in Huh7 cells and mouse liver\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with purified OGT and substrates plus MS site mapping, multiple deletion mutants tested; single lab\",\n      \"pmids\": [\"29772801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OGT1-catalyzed O-GlcNAcylation of AKT1 enhances AKT1 protein stability and promotes its binding with FOXO1; O-GlcNAcylated AKT1 promotes FOXO1 phosphorylation at Ser238, preventing FOXO1 nuclear entry and reducing gabarapl1 promoter activity, thereby inhibiting glycophagy.\",\n      \"method\": \"OGT1 knockdown, AKT1 stability assays, Co-IP of AKT1 and FOXO1, dual-luciferase reporter assay, ChIP at gabarapl1 promoter, 13C-labeled LC-MS metabolite analysis, high-carbohydrate diet fish model\",\n      \"journal\": \"The Journal of nutritional biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — multiple methods but primarily in a non-standard vertebrate model (fish); limited mechanistic validation of OGT1 as the canonical human OGT\",\n      \"pmids\": [\"36990368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Thermal proteome profiling reveals that O-GlcNAc bidirectionally regulates protein thermostability: 72 proteins display O-GlcNAc-dependent changes in stability, with the majority of O-GlcNAc-influenced proteins being destabilized rather than stabilized by the modification; destabilized proteins cluster into distinct macromolecular complexes.\",\n      \"method\": \"Thermal proteome profiling (TPP) comparing OGA inhibitor-treated vs. control cells, orthogonal validation of specific proteins\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteome-wide thermal shift assay with orthogonal validation; single lab, novel global mechanistic insight\",\n      \"pmids\": [\"35230102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OGT O-GlcNAcylation of MTA1 at Ser237/241/246 in adriamycin-adaptive breast cancer cells promotes MTA1 interaction with chromatin and its association with the NuRD complex, altering genome-wide binding to gene promoters and transcriptional regulation of genotoxic stress adaptation genes.\",\n      \"method\": \"Quantitative proteomics, ChIP-seq, transcriptome analysis, mutagenesis of MTA1 O-GlcNAc sites, Co-IP with NuRD complex components\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS site identification, ChIP-seq, and mutagenesis with functional gene expression readouts; single lab\",\n      \"pmids\": [\"34019948\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OGT is an essential mammalian enzyme that transfers a single O-GlcNAc moiety from UDP-GlcNAc onto serine/threonine residues of thousands of nuclear, cytoplasmic, and mitochondrial proteins, forming a scissor-shaped homodimer (cryo-EM structure) whose active site is mutually inhibited by OGA binding; beyond glycosylation, OGT proteolytically cleaves HCF-1 in the same active site and possesses an essential noncatalytic scaffolding function required for cell proliferation. OGT activity is regulated by USP8-mediated deubiquitination (protecting K117 from K48-linked degradation) and is transcriptionally controlled downstream of SIRT1-CREB signaling; OGT suppresses mTOR hyperactivation via proteasome inhibition, glycosylates and stabilizes substrates including c-Myc, SMAD4, RIPK3, S6K1, KAT5, and SNAP-29 to regulate autophagy, necroptosis, inflammation, and cancer metabolism, and modulates synaptic function, myelin integrity, and sensory neuron survival through tissue-specific substrate O-GlcNAcylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OGT is an essential glycosyltransferase that installs O-GlcNAc on serine/threonine residues of nuclear and cytoplasmic substrates to control protein stability, localization, and signaling across diverse cellular processes [#2, #25]. Cryo-EM and crystallographic studies define OGT as a scissor-shaped dimer whose extended substrate-binding groove accommodates peptide substrates, and within the OGT–OGA complex a flexible OGA segment occupies this groove while OGT occludes the OGA active site, establishing reciprocal inhibition that maintains O-GlcNAc homeostasis [#1, #16]. Beyond glycosylation, OGT's glycosyltransferase activity is required for mammalian cell proliferation while its HCF-1 protease activity is dispensable, and a noncatalytic scaffolding function — impacting oxidative phosphorylation and actin cytoskeleton proteins — is itself sufficient to sustain cell growth [#2, #12]. A recurring mechanistic theme is that OGT-catalyzed O-GlcNAcylation alters substrate fate: it stabilizes c-Myc (Ser415), SMAD4 (Thr63, by blocking GSK-3β-mediated degradation), and KAT5/TIP60 to drive cancer metabolism, TGF-β signaling, and metastasis, destabilizes RIPK3 to restrain necroptosis, and tunes enzyme activity such as eNOS dimerization and SLC7A11-mediated cystine import [#13, #15, #19, #4, #14, #3]; globally, O-GlcNAc bidirectionally regulates protein thermostability, more often destabilizing than stabilizing its targets [#25]. OGT also suppresses mTOR hyperactivation by restraining proteasome activity, and dampens macrophage proinflammatory signaling by O-GlcNAcylating S6K1 to block its phosphorylation [#6, #5]. Tissue-specific OGT loss produces distinct phenotypes — demyelinating neuropathy through mislocalized Periaxin, sensory neuron dieback, synaptic AMPA receptor and dendritic spine defects, astrocytic regulation of glutamate transport, and impaired pancreatic α- and β-cell function — reflecting substrate-specific roles in neural and metabolic tissues [#9, #10, #7, #8, #21, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a chromatin-targeting mechanism for OGT by showing it is recruited and stabilized through a direct protein partner, addressing how a promiscuous enzyme gains spatial specificity.\",\n      \"evidence\": \"Affinity purification/MS, Co-IP with TET3 deletion mutants, and chromatin fractionation\",\n      \"pmids\": [\"24304661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TET3 O-GlcNAcylation had no effect on TET3 5mC hydroxylation, leaving the functional consequence of the modification unclear\", \"whether other partners recruit OGT to chromatin not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed OGT regulates autophagy through SNARE glycosylation, linking nutrient-sensing O-GlcNAc to membrane fusion.\",\n      \"evidence\": \"OGT knockdown, SNAP-29 O-GlcNAc site mutagenesis, and autophagic flux assays in mammalian cells and C. elegans\",\n      \"pmids\": [\"25419848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"does not resolve how nutrient state quantitatively controls SNAP-29 modification stoichiometry\", \"structural basis of glycosylation impairing SNARE assembly not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the sequence determinants in HCF-1 that govern OGT's proteolytic versus glycosyltransferase outcomes within the same active site.\",\n      \"evidence\": \"Mutagenesis of HCF-1PRO cleavage sites with OGT binding and protease activity assays\",\n      \"pmids\": [\"26305326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"does not establish the physiological consequence of HCF-1 cleavage\", \"single-lab biochemical characterization\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a substrate-specific role for OGT in myelin maintenance by linking Periaxin O-GlcNAcylation to its correct localization.\",\n      \"evidence\": \"Schwann cell-specific OGT knockout, MS proteomics of sciatic nerve, PRX immunofluorescence, and electrophysiology\",\n      \"pmids\": [\"27629714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"does not prove PRX glycosylation alone accounts for the full neuropathy\", \"site of PRX O-GlcNAcylation and its direct effect on localization not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localized OGT to the postsynaptic density and demonstrated it is required for excitatory synapse composition and dendritic spine maturation, and separately that sensory neurons depend on OGT for survival.\",\n      \"evidence\": \"PSD fractionation, neuron- and sensory-neuron-specific OGT knockout, AMPA subunit immunostaining, spine and innervation quantification\",\n      \"pmids\": [\"28143929\", \"28115479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"specific synaptic substrates of OGT not identified\", \"molecular cause of axonal dieback preceding cell death not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended OGT's role to substrate stabilization in cancer and to substrate-recognition specificity, showing it glycosylates c-Myc (S415) to drive tumor metabolism and selectively recognizes a lamin A 'sweet spot.'\",\n      \"evidence\": \"Site-directed mutagenesis, ChIP, metabolic flux, xenografts; in vitro glycosylation of recombinant lamin tails with MS site mapping\",\n      \"pmids\": [\"38778217\", \"29772801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"determinants of OGT substrate selectivity remain largely empirical\", \"lamin A glycosylation's nuclear function not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked OGT to control of programmed necrosis by showing RIPK3 O-GlcNAcylation reduces its stability and restrains hepatocyte necroptosis.\",\n      \"evidence\": \"Liver-specific OGT knockout mice, RIPK3/MLKL immunoblotting, O-GlcNAcylation assays, histology\",\n      \"pmids\": [\"31672932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RIPK3 O-GlcNAc site not defined\", \"mechanism connecting glycosylation to degradation not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated OGT acts as a brake on inflammatory and signaling pathways via substrate modifications affecting phosphorylation, glycosylation of S6K1 suppressing mTORC1 and of eNOS controlling its dimerization and activity.\",\n      \"evidence\": \"Macrophage and tissue OGT knockouts, S6K1 and eNOS O-GlcNAc/phospho assays, dimerization and activity assays, mouse models\",\n      \"pmids\": [\"32601203\", \"32863226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"crosstalk between O-GlcNAc and phosphorylation sites mechanistically incomplete\", \"SIRT1-CREB control of OGT expression (Low confidence) not independently confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the essentiality logic of OGT by separating its glycosyltransferase, protease, and noncatalytic functions, and broadened its substrate network across DNA repair, metastasis, and pancreatic endocrine function.\",\n      \"evidence\": \"Separation-of-function complementation with degron depletion and proteomics; plus mutagenesis/Co-IP/ChIP studies on PARG, KAT5, MTA1, and conditional α/β-cell knockouts\",\n      \"pmids\": [\"33419956\", \"37858678\", \"34650217\", \"34019948\", \"33460647\", \"34462257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular identity of the noncatalytic scaffolding activity not defined\", \"how OGT coordinates so many substrates within one tissue unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a proteome-wide view showing O-GlcNAc bidirectionally tunes protein thermostability, reframing the modification as a broad regulator of complex assembly rather than uniformly stabilizing.\",\n      \"evidence\": \"Thermal proteome profiling comparing OGA-inhibitor-treated and control cells with orthogonal validation\",\n      \"pmids\": [\"35230102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether stability changes are direct or secondary not always resolved\", \"OGA inhibition reflects global O-GlcNAc, not OGT activity per se\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the structural basis of O-GlcNAc homeostasis through mutual OGT–OGA inhibition and placed OGT mechanistically upstream of mTOR via proteasome suppression.\",\n      \"evidence\": \"Cryo-EM of OGT alone and OGT–OGA complex; genome-wide CRISPR screen, phospho-proteomics, and mTOR/mitochondrial assays; USP8 deubiquitination of OGT\",\n      \"pmids\": [\"37907462\", \"36626549\", \"37867237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how the OGT–OGA setpoint is tuned in cells not established\", \"link between proteasome suppression and the noncatalytic essential function unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis of OGT's essential noncatalytic scaffolding function and the general rules governing its selection among thousands of substrates remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no defined structural/biochemical mechanism for the noncatalytic essential role\", \"no predictive substrate-recognition code beyond the dimer groove\", \"tissue-specific substrate prioritization not explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 13, 15, 23]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12, 2]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 25, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"OGA\", \"TET3\", \"HCF-1\", \"USP8\", \"GSK-3B\", \"PCNA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}