Affinage

OGT

UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit · UniProt O15294

Round 2 corrected
Length
1046 aa
Mass
116.9 kDa
Annotated
2026-04-29
130 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OGT is an essential X-linked glycosyltransferase that catalyzes the transfer of O-linked N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of thousands of nuclear and cytoplasmic substrates, thereby serving as a central nutrient-sensing hub that integrates metabolic status with signaling, transcription, protein stability, and chromatin regulation. Its N-terminal tetratricopeptide repeat (TPR) domain mediates substrate recognition and recruitment to chromatin (via TET2/TET3 interaction) or to the plasma membrane (via a PIP3-binding domain during insulin signaling), while a single catalytic center performs both glycosyltransferase and HCF-1 proteolytic cleavage activities (PMID:9083067, PMID:25336649, PMID:23222540, PMID:18288188). OGT suppresses proteasome activity to maintain low intracellular amino acid levels and prevent mTOR hyperactivation, acts cotranslationally to protect nascent polypeptides from premature degradation, and O-GlcNAcylates key substrates—including PFK1, RIPK3, c-Myc, Drp1, S6K1, and SLC7A11—to control glycolytic flux, necroptosis, mitochondrial dynamics, and ferroptosis sensitivity in a cell-type-specific manner (PMID:36626549, PMID:32870666, PMID:22923583, PMID:31672932, PMID:38778217, PMID:37867237). Missense mutations in the OGT TPR domain (e.g., L254F) cause X-linked intellectual disability by distorting the repeat structure and reducing catalytic activity (PMID:29606577).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    Molecular cloning revealed OGT as a novel nucleocytoplasmic glycosyltransferase with an unprecedented TPR-repeat architecture, establishing the enzymatic identity and domain organization underlying all subsequent functional studies.

    Evidence Molecular cloning, subcellular fractionation, and sequence analysis in mammalian and C. elegans systems by two independent groups

    PMID:9083067 PMID:9083068

    Open questions at the time
    • Substrate specificity determinants unknown
    • No structural information on TPR–substrate interactions
    • Physiological regulation of OGT activity uncharacterized
  2. 2000 High

    Genetic ablation demonstrated that OGT is essential for embryonic stem cell viability and mouse embryogenesis, placing it among indispensable housekeeping genes and motivating the search for essential substrates.

    Evidence Cre-loxP gene targeting and ZP3-Cre germline recombination in mouse ES cells and embryos

    PMID:10801981

    Open questions at the time
    • Which OGT substrates mediate the lethality was unknown
    • Catalytic versus noncatalytic requirements not distinguished
  3. 2008 High

    Discovery of a PIP3-binding domain in OGT showed how insulin signaling dynamically relocates OGT from the nucleus to the plasma membrane, where it O-GlcNAcylates insulin pathway components to attenuate signaling—providing a direct molecular link between O-GlcNAc and insulin resistance.

    Evidence Lipid-binding assays, subcellular fractionation upon insulin stimulation, and hepatic OGT overexpression in mice causing insulin resistance and dyslipidemia

    PMID:18288188

    Open questions at the time
    • Identity of all membrane-proximal OGT substrates not determined
    • Structural basis of PIP3-OGT interaction not resolved
  4. 2012 High

    The TET2/TET3–OGT interaction established that DNA demethylation enzymes recruit OGT to chromatin to catalyze histone H2B Ser112 O-GlcNAcylation, linking two major epigenetic systems and explaining how O-GlcNAc marks are deposited at specific genomic loci.

    Evidence Affinity purification, co-immunoprecipitation, ChIP, and TET2 knockdown reducing H2B S112 O-GlcNAc; confirmed for TET3 with domain mapping

    PMID:23222540 PMID:24304661

    Open questions at the time
    • Genome-wide map of TET-dependent OGT chromatin targets incomplete
    • Whether TET catalytic activity and OGT recruitment are coordinated at individual loci unclear
  5. 2012 High

    Site-specific O-GlcNAcylation of PFK1 at S529 under hypoxia was shown to redirect glycolytic flux into the pentose phosphate pathway, revealing OGT as a direct metabolic reprogramming switch in cancer cells.

    Evidence In vitro PFK1 activity assays, S529A mutagenesis, metabolic flux analysis, and xenograft tumor growth assays

    PMID:22923583

    Open questions at the time
    • Whether PFK1 glycosylation is reversible on physiological timescales not shown
    • Generality across cancer types not established
  6. 2014 High

    Structural and biochemical studies resolved the unexpected finding that OGT's glycosyltransferase and HCF-1 proteolytic cleavage activities share a single active site, establishing a dual-function catalytic mechanism unique among glycosyltransferases.

    Evidence X-ray crystallography combined with mutagenesis and biochemical activity assays

    PMID:25336649

    Open questions at the time
    • Regulation of the switch between glycosylation and cleavage modes not fully elucidated
    • Structural basis for HCF-1 specificity incompletely defined
  7. 2016 High

    Separation-of-function genetic complementation demonstrated that OGT's glycosyltransferase activity is required for cell growth while HCF-1 proteolysis is dispensable, and that catalytically dead OGT can rescue growth arrest in severely OGT-depleted cells, establishing an essential noncatalytic scaffolding role.

    Evidence Degron-tagged endogenous OGT with complementation by catalytic-dead or cleavage-defective variants, quantitative proteomics

    PMID:33419956

    Open questions at the time
    • Molecular identity of noncatalytic partners mediating the scaffolding function not identified
    • Whether scaffolding and catalytic functions are separable in vivo at physiological expression levels untested
  8. 2016 High

    Conditional knockout studies in forebrain and sensory neurons showed that OGT is required for neuronal survival and axonal maintenance in the adult brain, with loss causing neurodegeneration, tau hyperphosphorylation, and sensory neuropathy—establishing OGT as a neuroprotective factor beyond development.

    Evidence Forebrain- and sensory neuron-specific OGT KO mice with behavioral, histological, and biochemical analyses; human AD cortical tissue validation

    PMID:27956640 PMID:28115479

    Open questions at the time
    • Specific neuronal OGT substrates mediating neuroprotection largely unidentified
    • Causal versus correlative relationship with AD pathology not established
  9. 2017 High

    CaMKII phosphorylation of OGT in liver was shown to activate autophagy through Ulk/AMPK, revealing a calcium–OGT–autophagy signaling axis that controls hepatic glucose and ketone body production during fasting.

    Evidence Liver-specific OGT knockout mice, CaMKII-OGT kinase assays, autophagic flux measurements, metabolic phenotyping

    PMID:28903979

    Open questions at the time
    • CaMKII phosphorylation site(s) on OGT not fully mapped
    • Whether this axis operates in non-hepatic tissues unknown
  10. 2018 High

    The intellectual disability-associated L254F mutation was structurally shown to distort the TPR domain and reduce OGT catalytic activity, providing the first mechanistic explanation for OGT-linked neurodevelopmental disease.

    Evidence Crystal structure, molecular dynamics simulations, in vitro and cell-based OGT activity assays

    PMID:29606577

    Open questions at the time
    • Other XLID-associated OGT mutations not yet structurally characterized
    • Neurodevelopmental substrates affected by reduced activity not identified
  11. 2019 High

    OGT was found to O-GlcNAcylate RIPK3 and destabilize it, suppressing necroptosis; liver-specific OGT loss caused hepatocyte necroptosis leading to fibrosis and inflammation, linking OGT to a specific programmed cell death pathway.

    Evidence Liver-specific OGT KO mice, RIPK3 glycosylation and stability assays, histological analysis of liver pathology

    PMID:31672932

    Open questions at the time
    • Specific RIPK3 O-GlcNAcylation site(s) not mapped
    • Whether OGT suppresses necroptosis in non-hepatic cell types not determined
  12. 2020 High

    Bioorthogonal metabolic labeling demonstrated that OGT acts cotranslationally on nascent polypeptides, preventing their premature degradation—redefining O-GlcNAcylation as a protein quality-control modification rather than solely a post-translational regulatory mark.

    Evidence Tandem OPP + azido-GalNAc metabolic labeling, click chemistry enrichment, shotgun proteomics with targeted validation

    PMID:32870666

    Open questions at the time
    • Fraction of the proteome subject to cotranslational O-GlcNAcylation not quantified
    • Mechanism by which cotranslational O-GlcNAc prevents degradation not structurally resolved
  13. 2021 High

    A genome-wide CRISPR screen revealed that OGT maintains cell viability by suppressing proteasome activity, preventing amino acid accumulation and mTOR lysosomal hyperactivation, which otherwise impairs mitochondrial fitness—providing a unifying mechanism for OGT essentiality.

    Evidence Genome-wide CRISPR-Cas9 screen in mESCs, proteasome activity assays, mTOR translocation imaging, amino acid quantification, phospho-proteomics; replicated in CD8+ T cells

    PMID:36626549

    Open questions at the time
    • Direct OGT substrate(s) on the proteasome responsible for suppression not identified
    • How cells titrate proteasome O-GlcNAcylation in response to nutrient flux remains unclear
  14. 2022 High

    Cryo-EM structures of dimeric OGT and the OGT–OGA complex revealed mutual inhibition: OGA occupies OGT's substrate groove while OGT disrupts OGA's active dimer, explaining how futile O-GlcNAc cycling is limited to maintain homeostasis.

    Evidence Cryo-EM structure determination of human OGT dimer and OGT-OGA complex

    PMID:37907462

    Open questions at the time
    • Dynamics of OGT-OGA complex formation and dissociation in living cells not measured
    • Stoichiometry and regulation of the complex under different metabolic states not characterized
  15. 2023 High

    Multiple tissue-specific substrates were mechanistically resolved—including c-Myc S415 stabilization driving colorectal cancer metabolism, SLC7A11 S26 O-GlcNAcylation controlling cystine import and ferroptosis resistance, and GLT-1 glycosylation in astrocytes regulating glutamatergic transmission and depressive behaviors—demonstrating the breadth of OGT's cell-type-specific functional outputs.

    Evidence Site-directed mutagenesis, xenograft models, astrocyte-specific KO, electrophysiology, behavioral testing, ferroptosis and metabolic assays

    PMID:36757814 PMID:37867237 PMID:38778217

    Open questions at the time
    • Systematic catalog of cell-type-specific critical OGT substrates remains incomplete
    • Whether substrate specificity is determined primarily by TPR-mediated recruitment or by local substrate concentration unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis for TPR-mediated substrate selection among thousands of targets, the molecular identity of proteasomal OGT substrates mediating its essential proteasome-suppressive function, the full scope of cotranslational O-GlcNAcylation, and whether the noncatalytic scaffolding role of OGT can be therapeutically separated from its catalytic functions.
  • No comprehensive structural model for TPR–substrate selectivity
  • Noncatalytic scaffolding partners not molecularly identified
  • In vivo dynamics of OGT-OGA mutual inhibition not measured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 12 GO:0140096 catalytic activity, acting on a protein 2 GO:0008289 lipid binding 1
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3 GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-4839726 Chromatin organization 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1 R-HSA-9612973 Autophagy 1
Partners
GRHCF1MORC2OGARIPK3TET2TET3USP8
Complex memberships
NuRD complex (via MTA1)OGT-OGA regulatory complexTET2-OGT chromatin complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 OGT was cloned and characterized as a novel glycosyltransferase with multiple tetratricopeptide repeat (TPR) motifs, localized to the cytosol and nucleus, sharing no sequence homology with other glycosyltransferases. TPR repeats were proposed to mediate protein-protein interactions independent of the catalytic site. OGT was also found to be tyrosine-phosphorylated, implicating tyrosine kinase signaling in its regulation. Molecular cloning, sequence analysis, subcellular fractionation, biochemical characterization The Journal of biological chemistry High 9083067
1997 OGT is a conserved nucleocytoplasmic protein; the C. elegans ortholog accumulates in the nucleus and perinuclear aggregates. The human OGT gene produces at least four transcripts enriched in pancreas, and OGT activity is elevated in transfected HeLa cells. OGT was proposed to be part of a glucose-responsive pathway linked to diabetes pathogenesis. cDNA cloning, transgenic C. elegans overexpression, HeLa transfection, Northern blot The Journal of biological chemistry High 9083068
2000 OGT is encoded by a single X-linked gene (Xq13 in humans; near DxMit41/DxMit95 in mice). Homozygous deletion of OGT is lethal in embryonic stem cells, and intact OGT alleles are required for completion of mouse embryogenesis, establishing OGT as essential for embryonic stem cell viability and mouse ontogeny. Gene targeting (Cre-loxP), embryonic stem cell viability assay, ZP3-Cre germline recombination, genetic mapping Proceedings of the National Academy of Sciences of the United States of America High 10801981
2005 Fluorescence-based substrate-analogue displacement assays identified the first small-molecule inhibitors of OGT's catalytic domain, enabled by development of a bacterial expression system for large quantities of the OGT catalytic domain. Recombinant protein expression, fluorescence-based high-throughput inhibitor screen, in vitro enzyme assay Journal of the American Chemical Society High 16231908
2005 Ataxin-10 (SCA10 gene product) was identified as an OGT-interacting protein in pancreatic beta cells (MIN6 cells) and shown to be O-GlcNAc-modified by OGT in vivo, revealing a novel function for Ataxin-10 in beta cells. Yeast two-hybrid screen (cDNA library), co-immunoprecipitation in MIN6 cells, O-GlcNAc modification assay Biochemical and biophysical research communications Medium 16182253
2008 OGT harbors a phosphoinositide-binding domain; insulin signaling triggers PIP3-dependent recruitment of OGT from the nucleus to the plasma membrane. At the membrane, OGT O-GlcNAcylates insulin signaling components, altering their phosphorylation and attenuating insulin signal transduction. Hepatic OGT overexpression caused insulin resistance and dyslipidemia in mice. Lipid-binding domain identification, subcellular fractionation, co-immunoprecipitation, in vivo hepatic overexpression, insulin signaling assays Nature High 18288188
2008 O-GlcNAcylation regulates ubiquitination: increasing O-GlcNAc levels enhances ubiquitination, and OGT knockdown by RNAi reduces ubiquitination and halves cell thermotolerance. The ubiquitin-activating enzyme E1 was identified as an O-GlcNAc substrate, and its glycosylation state and interaction with Hsp70 varied with culture conditions. RNAi knockdown of OGT, glucosamine/PUGNAc pharmacological treatment, ubiquitination assays, co-immunoprecipitation (E1-Hsp70), heat stress survival assays FASEB journal Medium 18434435
2009 O-GlcNAc modification of Sp1 inhibits its physical interaction with the Elf-1 transcription factor, negatively regulating transcription of the Pem oncofetal gene, demonstrating that O-GlcNAcylation can modulate transcription factor cooperation. Co-immunoprecipitation, luciferase reporter assay, O-GlcNAc manipulation Biochemical and biophysical research communications Low 19285002
2010 OGT associates with glucocorticoid receptor (GR) in a ligand-dependent multi-protein repression complex at target gene promoters. OGT overexpression potentiates GR-mediated transrepression while OGT depletion abolishes it. GR-recruited OGT increases O-GlcNAcylation and decreases phosphorylation of RNA Polymerase II on target genes. Co-immunoprecipitation, RNAi knockdown, OGT overexpression, ChIP, RNA Pol II phosphorylation assays, apoptosis assays The Journal of biological chemistry Medium 22371499
2012 TET2 and TET3 directly interact with OGT; TET2 interaction promotes OGT chromatin association in vivo. TET2-OGT interaction facilitates OGT-dependent O-GlcNAcylation of histone H2B at Ser112. Downregulation of TET2 reduces H2B Ser112 O-GlcNAc marks associated with gene transcription. Protein affinity purification, co-immunoprecipitation, ChIP, H2B Ser112 O-GlcNAc assay, TET2 knockdown Nature High 23222540
2012 O-GlcNAcylation of phosphofructokinase 1 (PFK1) at serine 529 in response to hypoxia inhibits PFK1 activity and redirects glucose flux through the pentose phosphate pathway, conferring a growth advantage to cancer cells. Blocking this glycosylation reduced cancer cell proliferation and tumor formation in vivo. In vitro PFK1 enzyme activity assay, metabolic flux analysis, site-directed mutagenesis (S529A), xenograft tumor model, cell proliferation assays Science High 22923583
2013 TET3 interacts with OGT (identified by mass spectrometry and co-immunoprecipitation with deletion mutants); the C-terminal H domain of TET3 is required for this interaction. TET3 is O-GlcNAcylated by OGT (though this does not affect global 5mC hydroxylation activity). TET3 enhances OGT localization to chromatin by stabilizing OGT protein. Affinity purification-mass spectrometry, co-immunoprecipitation with deletion mutants, chromatin fractionation, O-GlcNAcylation assay Genes to cells Medium 24304661
2014 Structural and biochemical studies revealed the mechanism of OGT's dual enzymatic activities: catalytic glycosylation of Ser/Thr residues and proteolytic cleavage of HCF-1 (host cell factor 1, an essential cell cycle regulator) occur in the same active site. Structural analysis, biochemical activity assays, mutagenesis The Journal of biological chemistry High 25336649
2016 Forebrain-specific deletion of OGT in adult mice caused progressive neurodegeneration, including widespread neuronal cell death, neuroinflammation, hyperphosphorylated tau accumulation, amyloidogenic Aβ-peptide production, and memory deficits. Human AD cortical tissue showed significantly reduced OGT protein expression versus controls. Conditional OGT knockout (forebrain-specific Cre), histological analysis, tau phosphorylation assays, amyloid quantification, behavioral testing, human tissue immunoblot Proceedings of the National Academy of Sciences of the United States of America High 27956640
2016 OGT relocates to DNA double-strand break sites upon DNA damage, where it O-GlcNAcylates histone H2AX and MDC1. This O-GlcNAcylation negatively regulates DSB-induced phosphorylation of H2AX and MDC1, restraining the spatial expansion of the DNA damage phosphorylation response. Laser microirradiation, live-cell imaging, co-immunoprecipitation, O-GlcNAcylation assays, phosphorylation assays Nucleic acids research Medium 27458206
2016 OGT's glycosyltransferase function is required for mammalian cell growth but its HCF-1 protease function is dispensable. Additionally, when OGT is degraded to very low levels by degron tagging, cells stop proliferating but remain viable, and adding back catalytically inactive OGT rescues growth — establishing an essential noncatalytic structural role for OGT in cell proliferation. Genetic complementation with separation-of-function OGT variants, degron-tagged endogenous OGT, cell proliferation assays, quantitative proteomics Proceedings of the National Academy of Sciences of the United States of America High 33419956
2017 Upon glucagon-induced calcium signaling in liver, CaMKII phosphorylates OGT, which promotes OGT-dependent O-GlcNAcylation and activation of Ulk proteins by potentiating AMPK-dependent phosphorylation, driving autophagy. Liver-specific OGT KO reduces autophagic flux and production of glucose and ketone bodies during starvation. Liver-specific OGT knockout mice, kinase assays (CaMKII-OGT phosphorylation), co-immunoprecipitation, autophagic flux assays, metabolic measurements Genes & development High 28903979
2016 OGT is essential for sensory neuron survival and maintenance in mice. Sensory neuron-specific OGT knockout caused behavioral hyposensitivity, decreased epidermal innervation, and dorsal root ganglia cell-body loss progressing from axonal dieback to neuronal death. Adult-inducible OGT KO produced similar peripheral nerve-ending loss, demonstrating OGT is required for axonal maintenance independently of developmental roles. Conditional sensory neuron-specific OGT knockout, inducible adult KO, behavioral testing (thermal/mechanical thresholds), histological quantification, primary neuron culture axon outgrowth assay The Journal of neuroscience High 28115479
2018 The OGT intellectual disability mutation L254F causes conformational changes in the TPR helix, reducing OGT activity. Molecular dynamics and structural analyses show the mutation distorts the tetratricopeptide repeat domain, revealing the structural mechanism linking OGT TPR domain integrity to both catalytic activity and intellectual disability pathogenesis. Crystal structure/structural analysis, molecular dynamics simulations, in vitro OGT activity assays, cell-based assays Cell chemical biology High 29606577
2018 Thio-linked UDP-peptide conjugates act as potent bisubstrate OGT inhibitors (Ki = 1.3 μM for VTPVC(S-propyl-UDP)TA). A crystal structure of human OGT with the inhibitor revealed mimicry of interactions seen in the pseudo-Michaelis complex. Linear fusions with cell-penetrating peptides were explored as cell-penetrant inhibitor prototypes. Crystal structure of hOGT-inhibitor complex, fluorescence polarimetry assay, in vitro OGT inhibition, HeLa cell lysate activity assay Bioconjugate chemistry High 29723473
2019 Liver-specific OGT knockout mice develop spontaneous hepatomegaly, hepatocyte ballooning, liver fibrosis, and portal inflammation. OGT-deficient hepatocytes undergo excessive necroptosis with elevated RIPK3 and MLKL expression. OGT O-GlcNAcylates RIPK3, which is associated with reduced RIPK3 protein stability, establishing OGT as a suppressor of hepatocyte necroptosis. Liver-specific OGT KO mice, histology, RIPK3/MLKL immunoblotting, O-GlcNAcylation assay of RIPK3, protein stability assays JCI insight High 31672932
2019 OGT is localized to meiotic spindles in bovine oocytes (and conserved in human oocytes), while OGA is enriched at the cortex and O-GlcNAcylated proteins concentrate at the nuclear envelope at prophase I. Disruption of O-GlcNAc homeostasis during meiotic maturation impairs fertilization by affecting sperm penetration, sperm head decondensation, and pronuclear formation, without affecting meiotic progression itself. Immunofluorescence localization in bovine/human oocytes, OGA inhibitor (Thiamet-G) treatment, in vitro fertilization assay, meiotic progression analysis Molecular reproduction and development Medium 30793403
2020 OGT O-GlcNAcylates ribosomal S6 kinase beta-1 (S6K1), suppressing S6K1 phosphorylation and mTORC1 signaling, thereby inhibiting macrophage proinflammatory activation. Macrophage-specific OGT knockout enhances proinflammatory polarization, promotes adipose tissue inflammation, and exacerbates diet-induced insulin resistance. Macrophage-specific OGT knockout mice, high-fat diet model, S6K1 O-GlcNAcylation assays, phosphorylation assays, inflammatory marker quantification, metabolic phenotyping Proceedings of the National Academy of Sciences of the United States of America High 32601203
2020 SIRT1 deacetylates CREB, inhibiting CREB phosphorylation at Ser133, which suppresses OGT transcription, thereby reducing O-GlcNAcylation of tau and increasing tau phosphorylation at specific sites in neurons. SIRT1 deacetylation assay, CREB phosphorylation analysis, OGT expression assay, tau O-GlcNAcylation and phosphorylation quantification Aging Medium 32310828
2020 Tandem bioorthogonal labeling (OPP + Ac4GalNAz metabolic engineering) identified endogenous proteins that are cotranslationally O-GlcNAc-modified, demonstrating that OGT acts cotranslationally to modify nascent polypeptides and prevent their premature degradation, establishing O-GlcNAc as a cotranslational quality-control modification. Metabolic labeling (O-propargyl-puromycin + azido-GalNAc), tandem click chemistry, two-step enrichment, shotgun proteomics, targeted validation Journal of the American Chemical Society High 32870666
2020 O-GlcNAcylation of Drp1 (dynamin-related protein 1) occurs not only in the previously characterized variable domain but also in the GTPase domain, contributing to mitochondrial fission. OGA knockout cells show dramatically reduced mitochondrial size with increased numbers and mass, reduced complex I/II protein levels, and reduced complex I-III linked activity, revealing OGT-dependent regulation of mitochondrial dynamics and ETC function. OGA knockout cell lines, mitochondrial morphology imaging, ETC complex activity assays, O-GlcNAcylation mapping of Drp1 domains Scientific reports Medium 34764359
2021 OGT is essential for hematopoietic stem cell (HSC) maintenance. Ogt-deficient HSCs lose quiescence and accumulate defective mitochondria due to impaired PINK1-dependent mitophagy, caused by dysregulation of H3K4me3 at the Pink1 locus. PINK1 overexpression restores mitophagy and rescues Ogt-deficient HSC numbers. Ogt conditional knockout in hematopoietic cells, HSC quiescence analysis, mitochondrial ROS/apoptosis assays, H3K4me3 ChIP, PINK1 overexpression rescue Cell reports High 33406421
2021 OGT regulates β-cell mitochondrial morphology and function partly through the transcription factor Pdx1. Constitutive βOGT knockout causes swollen mitochondria, reduced glucose-stimulated oxygen consumption, ATP production, and glycolysis; Pdx1 is reduced in βOGTKO islets, and Pdx1 overexpression rescues mitochondrial morphology and insulin content. Constitutive and inducible β-cell specific OGT KO mice, mitochondrial morphology electron microscopy, oxygen consumption rate (Seahorse), ATP assay, islet proteomics, Pdx1 overexpression rescue Diabetes High 34462257
2021 OGT controls mammalian cell viability by suppressing proteasome activity, which maintains low steady-state amino acid levels and prevents mTOR lysosomal translocation and hyperactivation. In OGT-deficient cells, increased proteasome activity elevates amino acids, activates mTOR, and impairs mitochondrial fitness, blocking cell proliferation. A similar mechanism operates in CD8+ T cells. Genome-wide CRISPR-Cas9 screen in mESCs, proteasome activity assays, mTOR lysosomal translocation assay, phospho-proteomics, amino acid quantification, mitochondrial function assays Proceedings of the National Academy of Sciences of the United States of America High 36626549
2021 O-GlcNAcylation promotes nuclear chromatin association of MTA1 (metastasis-associated protein 1) at S237/S241/S246, enhancing its interaction with the NuRD complex and modulating transcription of genotoxic stress response genes in adriamycin-adaptive breast cancer cells. Quantitative proteomics, ChIP-seq, transcriptome analysis, OGT gain/loss-of-function, O-GlcNAc site mapping by MS Biochimica et biophysica acta. General subjects Medium 34019948
2021 OGT O-GlcNAcylates cerebral ischemia-related Drp1, increasing its Ser637 phosphorylation and preventing Drp1 translocation from cytosol to mitochondria. OGT knockdown in a mouse MCAO/R model increased neurological deficits, infarct volume, and neuronal apoptosis; the Drp1 inhibitor mdivi-1 rescued OGT knockdown-induced brain injury. OGT knockdown in MCAO/R mouse model, Drp1 phosphorylation assays, mitochondrial fractionation, TTC staining, TUNEL assay, pharmacological rescue with mdivi-1 Neuromolecular medicine Medium 34705256
2022 Cryo-EM structures of human OGT and the OGT-OGA complex revealed that OGT forms a functionally important scissor-shaped dimer. Within the OGT-OGA complex, an OGA segment occupies OGT's extended substrate-binding groove positioning a serine for O-GlcNAcylation (blocking other substrates), while OGT disrupts OGA's functional dimerization and occludes its active site — establishing mutual inhibition as a mechanism to limit futile O-GlcNAc cycling and maintain O-GlcNAc homeostasis. Cryo-electron microscopy structure determination of human OGT and OGT-OGA complex Nature communications High 37907462
2022 Thermal proteome profiling identified 72 proteins with O-GlcNAc-dependent thermostability changes; surprisingly, the majority of O-GlcNAc-influenced proteins are destabilized (not stabilized) by the modification, and destabilized proteins cluster into distinct macromolecular complexes, establishing O-GlcNAc as a bidirectional regulator of protein stability. Thermal proteome profiling (TPP), OGA inhibition to elevate O-GlcNAc, quantitative mass spectrometry, orthogonal protein stability validation Journal of the American Chemical Society High 35230102
2022 MORC2 is O-GlcNAcylated by OGT at threonine 556. TGF-β1 induces MORC2 O-GlcNAcylation by stabilizing GFAT (OGT sugar-donor biosynthetic enzyme). O-GlcNAcylated MORC2 activates transcription of CTGF and SNAIL to drive breast cancer cell migration and invasion; mutation of T556 or OGT inhibition impairs these phenotypes in vitro and lung colonization in vivo. Site-directed mutagenesis (T556A), co-immunoprecipitation, OGT inhibition, transwell migration/invasion assays, lung colonization xenograft, target gene expression analysis Cell death and differentiation High 34974534
2023 Astroglial OGT in the medial prefrontal cortex regulates depressive-like behaviors by O-GlcNAcylating glutamate transporter-1 (GLT-1), modulating glutamatergic synaptic transmission. Astrocytic OGT knockout preserved neuronal morphology and Ca2+ activity deficits caused by chronic stress and produced antidepressant effects. Astrocyte-specific OGT knockout, chronic social defeat stress model, GLT-1 O-GlcNAcylation assay, Ca2+ imaging, synaptic transmission electrophysiology, behavioral testing The Journal of clinical investigation High 36757814
2023 USP8 stabilizes OGT protein by inhibiting K48-linked poly-ubiquitination at OGT K117; SLK-mediated S716 phosphorylation of USP8 is required for its interaction with OGT. OGT in turn O-GlcNAcylates SLC7A11 at Ser26, which is essential for cystine import, and OGT destabilization upon USP8 inhibition decreases SLC7A11 O-GlcNAcylation, reducing cystine levels and inducing ferroptosis in hepatocellular carcinoma. Co-immunoprecipitation, site-directed mutagenesis, ubiquitination assays, O-GlcNAcylation assays (SLC7A11 Ser26), cystine import assay, ROS measurement, xenograft/metastasis models Advanced science High 37867237
2024 OGT O-GlcNAcylates c-Myc at serine 415, increasing c-Myc stability, which transcriptionally upregulates PDK2 expression. PDK2 phosphorylates and inhibits the pyruvate dehydrogenase complex, suppressing TCA cycle metabolism, reducing ROS, and promoting tumor growth in colorectal cancer. OGT depletion, c-Myc O-GlcNAcylation assay (S415), c-Myc stability assays, PDK2 expression analysis, PDH activity assay, TCA metabolic profiling, xenograft tumor model, clinical tissue correlation Cell death and differentiation High 38778217
2020 In Drosophila, OGT is both necessary and sufficient for Hipk (homeodomain-interacting protein kinase)-mediated tumor-like growth on a normal diet. OGT maintains Hipk protein stability by blocking proteasomal degradation; Hipk is directly O-GlcNAcylated by OGT. In mammalian cells, human HIPK2 accumulates posttranscriptionally upon OGT overexpression and is O-GlcNAcylated at S852, T1009, and S1147; mutations at these sites reduce HIPK2 O-GlcNAcylation and stability, demonstrating a conserved OGT-HIPK regulatory axis. Drosophila genetic epistasis, OGT overexpression/knockdown, HIPK2 mass spectrometry O-GlcNAc site mapping, site-directed mutagenesis, protein stability assays, proteasome inhibitor experiments Proceedings of the National Academy of Sciences of the United States of America High 31932432

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2014 Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 1868 25119034
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 1482 12150926
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2000 The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proceedings of the National Academy of Sciences of the United States of America 656 10801981
1997 Dynamic glycosylation of nuclear and cytosolic proteins. Cloning and characterization of a unique O-GlcNAc transferase with multiple tetratricopeptide repeats. The Journal of biological chemistry 628 9083067
2020 Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. Cell 587 32109412
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