Affinage

Showing OSGEP — KAE1 is a alias.

OSGEP

tRNA N6-adenosine threonylcarbamoyltransferase · UniProt Q9NPF4

Length
335 aa
Mass
36.4 kDa
Annotated
2026-06-10
41 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OSGEP (KAE1) is the catalytic subunit of the evolutionarily conserved KEOPS/EKC complex, where its essential role is the biosynthesis of N6-threonylcarbamoyladenosine (t6A) at position 37 of tRNAs decoding ANN codons, a modification required for accurate start-codon selection and prevention of frameshifting at tandem ANN codons (PMID:21285948, PMID:26516084). The protein adopts an ASKHA fold and is an iron-binding protein whose physical association with the Bud32/PRPK kinase subunit holds that kinase in an inactive state; disruption of the Kae1/Bud32 interface abolishes both transcription and telomere homeostasis functions of the complex (PMID:19172740). Within the complex Kae1 itself carries an ADP/GDP nucleotidase activity that is separable from t6A synthesis and instead contributes specifically to telomere length regulation (PMID:36416748). The t6A function has direct physiological consequences for translational fidelity: in pancreatic β-cells, loss of OSGEP impairs proinsulin translation, causing accumulation of misfolded proinsulin, activation of the unfolded protein response, apoptosis, and glucose intolerance, while OSGEP overexpression rescues insulin secretion (PMID:39622811). Pathogenic OSGEP variants cause Galloway-Mowat syndrome by reducing t6A levels and disrupting global protein synthesis (PMID:28272532), and patient-derived variants additionally reduce OSGEP protein, mislocalize it to the cytosol, and activate the DNA damage response (PMID:34666032). Reported ferroptosis-suppressing and N-CoR protease activities of mammalian OSGEP have not been corroborated beyond single low-confidence studies in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2007 Medium

    Established the first biochemical activities of the OSGEP family by showing the archaeal ortholog is an iron metalloprotein with ATP-modulated DNA-binding and AP-endonuclease/AP-lyase activity, framing an early DNA-associated rather than tRNA-associated hypothesis.

    Evidence Protein purification and in vitro DNA-binding/AP-endonuclease assays, EPR and metal analysis of purified archaeal Kae1

    PMID:17766251

    Open questions at the time
    • Studied the archaeal ortholog, not mammalian OSGEP
    • In vitro DNA activities not connected to the later-established t6A function
    • Single lab
  2. 2009 Medium

    Showed that mitochondrial paralogs (Qri7/OSGEPL) localize to mitochondria and maintain the mitochondrial genome, distinguishing a paralogous mitochondrial branch from cytoplasmic OSGEP.

    Evidence Fluorescence localization, genetic complementation and mitochondrial genome maintenance assays in yeast and C. elegans

    PMID:19578062

    Open questions at the time
    • Concerns the mitochondrial paralog OSGEPL, not cytoplasmic OSGEP
    • Does not address t6A biosynthesis directly
  3. 2009 High

    Defined the structural fold and intracomplex regulatory logic, demonstrating Kae1 adopts an ASKHA iron-protein fold and represses Bud32/PRPK kinase activity, with the interface required for transcription and telomere functions in vivo.

    Evidence X-ray crystallography of an archaeal Kae1/Bud32 fusion, in vitro kinase assay, mutagenesis and yeast genetics

    PMID:19172740

    Open questions at the time
    • Mechanism by which kinase repression couples to t6A synthesis not resolved
    • Telomere function mechanism left undefined at this stage
  4. 2011 High

    Identified the core conserved function: OSGEP/Kae1 is required for t6A synthesis at tRNA position 37, with loss causing initiation-codon and frameshifting defects, establishing the link to translational fidelity.

    Evidence Yeast null mutant analysis, comparative genomics, structural analysis and tRNA modification assays

    PMID:21285948

    Open questions at the time
    • Catalytic mechanism of t6A transfer within the complex not fully dissected
    • Did not establish mammalian disease relevance
  5. 2015 High

    Confirmed conservation of the t6A function in a metazoan and revealed differential tissue sensitivity, with proliferating tissues most vulnerable to t6A loss.

    Evidence Drosophila allelic series, tRNA modification quantification, yeast complementation and clonal analysis

    PMID:26516084

    Open questions at the time
    • Molecular basis of proliferative-tissue sensitivity not defined
    • No mammalian in vivo confirmation in this study
  6. 2017 High

    Connected OSGEP to human disease by showing a pathogenic variant reduces t6A and fails to rescue yeast t6A deficiency, linking Galloway-Mowat syndrome to disrupted t6A biosynthesis.

    Evidence Exome sequencing, yeast complementation and LC-MS/MS quantification of t6A

    PMID:28272532

    Open questions at the time
    • Tissue-specific basis of the renal/neurological phenotype not explained
    • Effects on specific tRNAs not enumerated
  7. 2019 Medium

    Linked t6A status to nutrient signaling by validating KAE1 as a determinant of TORC1 activation by glutamine and of fermentation under low nitrogen.

    Evidence QTL mapping, reciprocal hemizygous analysis, TORC1 activation and fermentation assays in yeast

    PMID:31417508

    Open questions at the time
    • Mechanism connecting t6A to TORC1 not defined
    • Yeast-specific; not confirmed in mammalian cells
  8. 2022 High

    Separated two activities of Kae1, attributing ADP/GDP nucleotidase activity to Kae1 itself and assigning it specifically to telomere length regulation distinct from t6A synthesis.

    Evidence Recombinant complex reconstitution, in vitro nucleotidase assays, mutagenesis and yeast telomere assays

    PMID:36416748

    Open questions at the time
    • How nucleotidase activity mechanistically influences telomeres unknown
    • Demonstrated in yeast complex; mammalian relevance untested
  9. 2024 High

    Placed OSGEP t6A function in a mammalian physiological pathway by showing β-cell OSGEP loss impairs proinsulin translational fidelity, triggers UPR and apoptosis, and causes hyperglycemia, with overexpression rescuing insulin secretion.

    Evidence Global and β-cell-specific knockout mice, transcriptomics/proteomics, insulin secretion and UPR assays, overexpression rescue

    PMID:39622811

    Open questions at the time
    • Specific mistranslated codons in proinsulin not enumerated
    • Whether non-β-cell tissues share this UPR axis untested
  10. 2021 Medium

    Characterized human disease variants at the cellular level, showing reduced OSGEP protein, cytosolic mislocalization/aggregation, and DNA damage response activation.

    Evidence Patient lymphoblastoid lines, confocal microscopy of tagged mutants, western blot and DDR analysis

    PMID:34666032

    Open questions at the time
    • Whether DDR activation is a direct OSGEP function or downstream of t6A loss unresolved
    • Single lab, limited mechanistic follow-up
  11. 2025 Medium

    Proposed a non-canonical neuronal role in which OSGEP suppresses ferroptosis by modulating m6A methylation of GPX4 mRNA via competition with YTHDC1 and complex formation with HNRNPUL1.

    Evidence MCAO/OGD-R models, gain/loss-of-function, m6A analysis, RIP and co-IP

    PMID:40100474

    Open questions at the time
    • m6A-GPX4 axis not reconstituted in vitro
    • Relationship to canonical t6A enzymatic role unclear
    • Single lab
  12. 2024 Low

    Reported that OSGEP overexpression protects against hepatic ischemia-reperfusion ferroptosis through MEK/ERK signaling.

    Evidence Mouse HIRI and OGD/R cell models with ERK1/2 rescue experiments

    PMID:38456959

    Open questions at the time
    • Biochemical link between OSGEP and MEK/ERK not defined
    • Single lab; not independently confirmed
  13. 2025 Low

    Revived an endopeptidase hypothesis by reporting an OSGEP protease form cleaving N-CoR in AML-M5 cells, a claim that conflicts with the established t6A enzymatic role.

    Evidence HPLC isolation, mass spectrometry, in vitro protease assay and transfection studies

    PMID:40796998

    Open questions at the time
    • Not independently replicated
    • No mutagenesis/reconstitution controls described
    • Contradicts the established and well-supported t6A enzyme function

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the multiple reported mammalian OSGEP activities (t6A synthesis, telomere-linked nucleotidase, m6A/GPX4 regulation, MEK/ERK signaling, N-CoR protease) mechanistically relate, and whether the non-canonical activities are direct or secondary to t6A-dependent translational changes.
  • No unified biochemical model linking t6A loss to ferroptosis or DDR phenotypes
  • Non-canonical activities reported only in single low-confidence studies
  • Mammalian KEOPS complex structure-function not directly addressed in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 2 GO:0003723 RNA binding 1 GO:0016787 hydrolase activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-8953854 Metabolism of RNA 2
Partners
BUD32HNRNPUL1YTHDC1
Complex memberships
KEOPS/EKC complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 OSGEP (Kae1) is required for biosynthesis of N6-threonylcarbamoyl adenosine (t6A), a universal modification at position 37 of tRNAs decoding ANN codons; yeast kae1Δ mutants are completely devoid of t6A, and t6A loss causes initiation codon restriction failure and frameshifting at tandem ANN codons. Yeast mutant analysis, comparative genomics, structural analysis, functional complementation, tRNA modification assays The EMBO journal High 21285948
2007 Archaeal Kae1 (ortholog of OSGEP) is an iron metalloprotein with an atypical ATP-binding site that binds cooperatively to single- and double-stranded DNA, induces unusual DNA conformational changes, and exhibits class I apurinic (AP)-endonuclease/AP-lyase activity in vitro; both DNA binding and AP-endonuclease activity are inhibited by ATP; no endopeptidase activity was detected. Protein purification, in vitro biochemical assays (DNA binding, AP-endonuclease assay), EPR, metal analysis Nucleic acids research Medium 17766251
2008 Crystal structure of the archaeal Kae1/Bud32 fusion protein MJ1130 shows that Kae1 has an ASKHA fold and is an iron protein, and that its association with Bud32 (the PRPK ortholog) maintains Bud32's kinase in an inactive state; yeast Kae1p was shown to repress the kinase activity of yeast Bud32p in vitro; mutations disrupting the Kae1p/Bud32p interaction abolish both transcription and telomere homeostasis functions of the EKC/KEOPS complex in vivo. X-ray crystallography, in vitro kinase assay, site-directed mutagenesis, yeast genetic studies The EMBO journal High 19172740
2009 Yeast Qri7 and human OSGEPL (mitochondrial paralogs of OSGEP/Kae1 family) localize to mitochondria and are required for mitochondrial genome maintenance in S. cerevisiae and C. elegans; yeast Qri7 complements loss of bacterial YgjD in E. coli, indicating functional conservation. Subcellular fractionation/localization (fluorescence microscopy), genetic complementation, mitochondrial genome maintenance assays Nucleic acids research Medium 19578062
2017 A homozygous p.Arg325Gln mutation in KAE1/OSGEP reduces t6A modification levels (measured by LC-MS/MS) and fails to efficiently rescue t6A deficiency in kae1Δ yeast, demonstrating that OSGEP pathogenic variants cause disease by perturbing t6A tRNA biosynthesis and thereby interfering with global protein production. Exome sequencing, yeast complementation, LC-MS/MS quantification of t6A levels European journal of human genetics High 28272532
2015 Drosophila Kae1 (ortholog of OSGEP) is required for t6A modification of tRNAs; kae1 hemizygous larvae show t6A decreases correlating with allele strength; Drosophila Kae1 and other t6A factors complement corresponding yeast null mutants, confirming conserved t6A synthesis function; strongly mitotic tissues (imaginal discs) are exquisitely sensitive to kae1 loss, whereas non-proliferating tissues are less affected. Drosophila genetic allelic series, tRNA modification analysis, yeast complementation, clonal analysis RNA (New York, N.Y.) High 26516084
2019 In S. cerevisiae, KAE1 allelic variants affect TORC1 pathway activation; reciprocal hemizygous analysis validated KAE1 as a gene responsible for natural variation in TORC1 activation by glutamine, and KAE1 hemizygous strains showed altered fermentation kinetics under low nitrogen conditions, linking tRNA t6A modification to TORC1 signaling and nitrogen metabolism. QTL mapping, reciprocal hemizygous analysis, TORC1 activation assay, fermentation kinetics measurement Frontiers in microbiology Medium 31417508
2022 In the yeast KEOPS complex, Kae1 (not Bud32) is responsible for ADP/GDP nucleotidase activity (hydrolyzing ADP to adenosine or GDP to guanosine with PPi production); mutagenesis of Kae1 (V309D) reduces ADP/GDP nucleotidase activity in vitro and shortens telomeres in vivo but shows only limited defect in t6A modification, suggesting this nucleotidase activity contributes specifically to telomere length regulation. Recombinant protein purification, in vitro nucleotidase/ATPase/GTPase assays, site-directed mutagenesis, yeast telomere length assays The Biochemical journal High 36416748
2024 OSGEP is required for t6A37 modification of tRNANNU in pancreatic β-cells; global or β-cell-specific Osgep deletion in mice causes glucose intolerance/hyperglycemia by impairing proinsulin translational fidelity, leading to accumulation of misfolded proinsulin, activation of the unfolded protein response (UPR) and apoptosis; Osgep overexpression in pancreas rescues insulin secretion and mitigates diabetes in high-fat diet mice. Conditional knockout mice, transcriptomics, proteomics, insulin secretion assays, UPR pathway analysis, overexpression rescue experiments Nature communications High 39622811
2021 Novel compound heterozygous OSGEP variants (c.133dupA; c.608C>T) reduce OSGEP protein expression, activate DNA damage response (DDR) signaling in patient lymphoblastoid cell lines, and cause abnormal protein localization — one mutant forms cytosolic aggregates and another is retained in the cytosol — as shown by confocal microscopy with EGFP/HA-tagged constructs. Patient-derived lymphoblastoid cell lines, confocal microscopy with tagged mutant proteins, western blot, DDR signaling analysis Clinica chimica acta Medium 34666032
2025 OSGEP suppresses ferroptosis in neurons by regulating GPX4 expression through modulation of m6A methylation of GPX4 mRNA; OSGEP competes with YTHDC1 for binding to GPX4 mRNA and forms a complex with HNRNPUL1; OSGEP knockout exacerbates ferroptotic cell death in MCAO/OGD-R models, while overexpression is protective. MCAO mouse model, OGD/R neuronal cultures, gain- and loss-of-function experiments, m6A methylation analysis, RNA immunoprecipitation, co-immunoprecipitation Neurochemical research Medium 40100474
2024 OSGEP overexpression protects against hepatic ischemia-reperfusion injury-induced ferroptosis by activating the MEK/ERK signaling pathway; ERK1/2 knockdown or overexpression reversed the effects of OSGEP manipulation on ferroptotic cell death in OGD/R-treated HepG2 cells and a mouse HIRI model. Mouse HIRI model, OGD/R cell model, gain- and loss-of-function, ERK1/2 rescue experiments, ALT/AST measurements Molecular biotechnology Low 38456959
2002 The human OSGEP gene (encoding a putative O-sialoglycoprotein endopeptidase homologous to Pasteurella haemolytica glycoprotease gcp) shares a bidirectional promoter with the adjacent APEX gene; a CCAAT box within a CpG island was identified as the functional element required for full transcriptional activity of both genes by luciferase reporter assay. cDNA/genomic cloning, sequencing, luciferase promoter assay in HeLa cells, Northern blot Gene Low 12039036
2025 In AML-M5 cells, a functionally active form of OSGEP protease was isolated by HPLC and confirmed by mass spectrometry to cleave the transcriptional co-repressor N-CoR in vitro; transfection studies showed that OSGEP selectively degrades N-CoR in AML-M5 cells but not in other cell types, suggesting subtype-specific protease activity. HPLC size exclusion chromatography, mass spectrometry, in vitro protease assay with recombinant N-CoR, transfection studies across cell lines Biotechnology letters Low 40796998

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 A role for the universal Kae1/Qri7/YgjD (COG0533) family in tRNA modification. The EMBO journal 138 21285948
2004 Regions of human kidney anion exchanger 1 (kAE1) required for basolateral targeting of kAE1 in polarised kidney cells: mis-targeting explains dominant renal tubular acidosis (dRTA). Journal of cell science 94 14996906
2017 tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy. European journal of human genetics : EJHG 74 28272532
2002 Impaired trafficking of distal renal tubular acidosis mutants of the human kidney anion exchanger kAE1. American journal of physiology. Renal physiology 72 11934690
2007 An archaeal orthologue of the universal protein Kae1 is an iron metalloprotein which exhibits atypical DNA-binding properties and apurinic-endonuclease activity in vitro. Nucleic acids research 63 17766251
2002 Impaired trafficking of human kidney anion exchanger (kAE1) caused by hetero-oligomer formation with a truncated mutant associated with distal renal tubular acidosis. The Biochemical journal 58 12227829
2008 Structure of the archaeal Kae1/Bud32 fusion protein MJ1130: a model for the eukaryotic EKC/KEOPS subcomplex. The EMBO journal 55 19172740
2009 Qri7/OSGEPL, the mitochondrial version of the universal Kae1/YgjD protein, is essential for mitochondrial genome maintenance. Nucleic acids research 54 19578062
2004 Trafficking defects of a novel autosomal recessive distal renal tubular acidosis mutant (S773P) of the human kidney anion exchanger (kAE1). The Journal of biological chemistry 46 15252044
2009 The universal Kae1 protein and the associated Bud32 kinase (PRPK), a mysterious protein couple probably essential for genome maintenance in Archaea and Eukarya. Biochemical Society transactions 32 19143597
2002 Sequencing analysis of a putative human O-sialoglycoprotein endopeptidase gene (OSGEP) and analysis of a bidirectional promoter between the OSGEP and APEX genes. Gene 24 12039036
2018 Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype. Orphanet journal of rare diseases 22 30558655
2007 Interaction of integrin-linked kinase with the kidney chloride/bicarbonate exchanger, kAE1. The Journal of biological chemistry 22 17553790
2019 Novel homozygous OSGEP gene pathogenic variants in two unrelated patients with Galloway-Mowat syndrome: case report and review of the literature. BMC nephrology 21 30975089
2015 An extensive allelic series of Drosophila kae1 mutants reveals diverse and tissue-specific requirements for t6A biogenesis. RNA (New York, N.Y.) 21 26516084
2006 Trafficking defect of mutant kidney anion exchanger 1 (kAE1) proteins associated with distal renal tubular acidosis and Southeast Asian ovalocytosis. Biochemical and biophysical research communications 15 17027918
2008 Structural characterization of the cytosolic domain of kidney chloride/bicarbonate anion exchanger 1 (kAE1). Biochemistry 13 18358003
2019 KAE1 Allelic Variants Affect TORC1 Activation and Fermentation Kinetics in Saccharomyces cerevisiae. Frontiers in microbiology 12 31417508
2018 Nephrological and urological complications of homozygous c.974G>A (p.Arg325Gln) OSGEP mutations. Pediatric nephrology (Berlin, Germany) 11 30141175
2014 Kinase-associated endopeptidase 1 (Kae1) participates in an atypical ribosome-associated complex in the apicoplast of Plasmodium falciparum. The Journal of biological chemistry 11 25204654
2022 Galloway-Mowat Syndrome Type 3 Caused by OSGEP Gene Variants: A Case Report and Literature Review. Frontiers in pediatrics 10 35783322
2021 Novel variants in OSGEP leading to Galloway-Mowat syndrome by altering its subcellular localization. Clinica chimica acta; international journal of clinical chemistry 10 34666032
2018 Identification of erythrocyte membrane proteins interacting with Mycoplasma suis GAPDH and OSGEP. Research in veterinary science 10 29890385
2024 OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice. Nature communications 9 39622811
2017 PDLIM5 links kidney anion exchanger 1 (kAE1) to ILK and is required for membrane targeting of kAE1. Scientific reports 8 28045035
2016 Loss of kAE1 expression in collecting ducts of end-stage kidneys from a family with SLC4A1 G609R-associated distal renal tubular acidosis. Clinical kidney journal 8 28638614
2014 Role of adaptor proteins and clathrin in the trafficking of human kidney anion exchanger 1 (kAE1) to the cell surface. Traffic (Copenhagen, Denmark) 8 24698155
2004 Human kanadaptin and kidney anion exchanger 1 (kAE1) do not interact in transfected HEK 293 cells. Molecular membrane biology 7 15764369
2015 Transmembrane protein 139 (TMEM139) interacts with human kidney isoform of anion exchanger 1 (kAE1). Biochemical and biophysical research communications 5 26049106
2017 γ-COPI mediates the retention of kAE1 G701D protein in Golgi apparatus - a mechanistic explanation of distal renal tubular acidosis associated with the G701D mutation. The Biochemical journal 4 28646128
1999 Genomic structure of the rat major AP endonuclease gene (Apex) with an adjacent putative O-sialoglycoprotease gene (Prsmg1/Gcpl1) and a processed Apex pseudogene (Apexp1). Acta medica Okayama 4 10631378
2025 OSGEP, A Negative Ferroptotic Regulator, Alleviates Cerebral Ischemia-Reperfusion Injury Through Modulating m6A Methylation of GPX4 mRNA. Neurochemical research 3 40100474
2024 O-sialoglycoprotein Endopeptidase (OSGEP) Suppresses Hepatic Ischemia-Reperfusion Injury-Induced Ferroptosis Through Modulating the MEK/ERK Signaling Pathway. Molecular biotechnology 3 38456959
2023 Whole-exome sequencing revealed a novel homozygous missense variant in OSGEP gene: a case report of Galloway-Mowat syndrome in Iran. CEN case reports 3 36856752
2022 Kae1 of Saccharomyces cerevisiae KEOPS complex possesses ADP/GDP nucleotidase activity. The Biochemical journal 3 36416748
2018 Treacher Collins syndrome 3 (TCS3)-associated POLR1C mutants are localized in the lysosome and inhibits chondrogenic differentiation. Biochemical and biophysical research communications 3 29567474
2024 Galloway-mowat syndrome 3 (GAMOS3): a novel disease-causing variant in OSGEP gene and expansion of the clinical spectrum. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2 39661309
2024 Unraveling the molecular landscape of kAE1: a narrative review. Canadian journal of physiology and pharmacology 1 38669699
2018 Adaptor protein 1 B mu subunit does not contribute to the recycling of kAE1 protein in polarized renal epithelial cells. Molecular membrane biology 1 29651904
2026 OSGEP-Associated Galloway-Mowat Syndrome: A Longitudinal Genotype-Phenotype Correlation from Prenatal Imaging Markers to Lifespan Neurologic-Renal Trajectories. QJM : monthly journal of the Association of Physicians 0 41795827
2025 Identification and characterisation of subtype-specific anti-N-CoR OSGEP protease in acute myeloid leukaemia (AML-M5) cell lineage. Biotechnology letters 0 40796998

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