{"gene":"OSGEP","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2011,"finding":"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.","method":"Yeast mutant analysis, comparative genomics, structural analysis, functional complementation, tRNA modification assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical phenotype (t6A loss) in null mutants, replicated with multiple genetic and biochemical approaches, foundational paper widely cited","pmids":["21285948"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Protein purification, in vitro biochemical assays (DNA binding, AP-endonuclease assay), EPR, metal analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro reconstitution with purified archaeal ortholog, but single lab, and this is the archaeal ortholog not mammalian OSGEP","pmids":["17766251"],"is_preprint":false},{"year":2008,"finding":"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.","method":"X-ray crystallography, in vitro kinase assay, site-directed mutagenesis, yeast genetic studies","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with in vitro kinase assay and mutagenesis with in vivo functional validation, single lab but multiple orthogonal methods","pmids":["19172740"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Subcellular fractionation/localization (fluorescence microscopy), genetic complementation, mitochondrial genome maintenance assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence in two model organisms, but study concerns the mitochondrial paralog (OSGEPL) not cytoplasmic OSGEP","pmids":["19578062"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Exome sequencing, yeast complementation, LC-MS/MS quantification of t6A levels","journal":"European journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct biochemical quantification of t6A by LC-MS/MS combined with genetic complementation in yeast, multiple orthogonal methods in single study","pmids":["28272532"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Drosophila genetic allelic series, tRNA modification analysis, yeast complementation, clonal analysis","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — extensive allelic series in Drosophila with direct t6A quantification and yeast complementation; tissue-specific phenotype established by clonal analysis; multiple orthogonal methods","pmids":["26516084"],"is_preprint":false},{"year":2019,"finding":"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.","method":"QTL mapping, reciprocal hemizygous analysis, TORC1 activation assay, fermentation kinetics measurement","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal hemizygous validation with phenotypic readouts in two separate assays, single lab","pmids":["31417508"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Recombinant protein purification, in vitro nucleotidase/ATPase/GTPase assays, site-directed mutagenesis, yeast telomere length assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with purified recombinant complexes and mutagenesis, functional in vivo validation of telomere phenotype, multiple orthogonal methods in single study","pmids":["36416748"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Conditional knockout mice, transcriptomics, proteomics, insulin secretion assays, UPR pathway analysis, overexpression rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vivo approaches (global KO, conditional KO, OE rescue) with mechanistic pathway placement linking t6A modification to translational fidelity and UPR","pmids":["39622811"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Patient-derived lymphoblastoid cell lines, confocal microscopy with tagged mutant proteins, western blot, DDR signaling analysis","journal":"Clinica chimica acta","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — direct localization experiment with functional consequence (DDR activation), single lab, limited mechanistic follow-up beyond localization","pmids":["34666032"],"is_preprint":false},{"year":2025,"finding":"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.","method":"MCAO mouse model, OGD/R neuronal cultures, gain- and loss-of-function experiments, m6A methylation analysis, RNA immunoprecipitation, co-immunoprecipitation","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — multiple in vivo/in vitro methods but single lab, mechanistic pathway (m6A-GPX4) supported by RIP and co-IP but not fully reconstituted","pmids":["40100474"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Mouse HIRI model, OGD/R cell model, gain- and loss-of-function, ERK1/2 rescue experiments, ALT/AST measurements","journal":"Molecular biotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological/genetic rescue establishes pathway placement but mechanism linking OSGEP to MEK/ERK is not biochemically defined","pmids":["38456959"],"is_preprint":false},{"year":2002,"finding":"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.","method":"cDNA/genomic cloning, sequencing, luciferase promoter assay in HeLa cells, Northern blot","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional promoter mapping by reporter assay, single lab, no direct protein functional characterization","pmids":["12039036"],"is_preprint":false},{"year":2025,"finding":"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.","method":"HPLC size exclusion chromatography, mass spectrometry, in vitro protease assay with recombinant N-CoR, transfection studies across cell lines","journal":"Biotechnology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, novel protease claim for mammalian OSGEP that contradicts the established t6A enzyme function; not independently replicated; abstract does not describe rigorous mutagenesis or reconstitution controls","pmids":["40796998"],"is_preprint":false}],"current_model":"OSGEP (KAE1) is the catalytic subunit of the evolutionarily conserved KEOPS complex responsible for biosynthesis of N6-threonylcarbamoyl adenosine (t6A) at position 37 of tRNAs decoding ANN codons, a modification essential for translational fidelity; structurally, it adopts an ASKHA fold, binds iron, carries ADP/GDP nucleotidase activity contributing to telomere maintenance, and physically interacts with and inhibits the kinase activity of the Bud32/PRPK subunit; loss of OSGEP impairs proinsulin translation and activates the unfolded protein response in pancreatic β-cells, and pathogenic OSGEP variants cause Galloway-Mowat syndrome by reducing t6A levels and disrupting global protein synthesis."},"narrative":{"mechanistic_narrative":"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.","teleology":[{"year":2007,"claim":"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","pmids":["17766251"],"confidence":"Medium","gaps":["Studied the archaeal ortholog, not mammalian OSGEP","In vitro DNA activities not connected to the later-established t6A function","Single lab"]},{"year":2009,"claim":"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","pmids":["19578062"],"confidence":"Medium","gaps":["Concerns the mitochondrial paralog OSGEPL, not cytoplasmic OSGEP","Does not address t6A biosynthesis directly"]},{"year":2009,"claim":"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","pmids":["19172740"],"confidence":"High","gaps":["Mechanism by which kinase repression couples to t6A synthesis not resolved","Telomere function mechanism left undefined at this stage"]},{"year":2011,"claim":"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","pmids":["21285948"],"confidence":"High","gaps":["Catalytic mechanism of t6A transfer within the complex not fully dissected","Did not establish mammalian disease relevance"]},{"year":2015,"claim":"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","pmids":["26516084"],"confidence":"High","gaps":["Molecular basis of proliferative-tissue sensitivity not defined","No mammalian in vivo confirmation in this study"]},{"year":2017,"claim":"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","pmids":["28272532"],"confidence":"High","gaps":["Tissue-specific basis of the renal/neurological phenotype not explained","Effects on specific tRNAs not enumerated"]},{"year":2019,"claim":"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","pmids":["31417508"],"confidence":"Medium","gaps":["Mechanism connecting t6A to TORC1 not defined","Yeast-specific; not confirmed in mammalian cells"]},{"year":2022,"claim":"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","pmids":["36416748"],"confidence":"High","gaps":["How nucleotidase activity mechanistically influences telomeres unknown","Demonstrated in yeast complex; mammalian relevance untested"]},{"year":2024,"claim":"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","pmids":["39622811"],"confidence":"High","gaps":["Specific mistranslated codons in proinsulin not enumerated","Whether non-β-cell tissues share this UPR axis untested"]},{"year":2021,"claim":"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","pmids":["34666032"],"confidence":"Medium","gaps":["Whether DDR activation is a direct OSGEP function or downstream of t6A loss unresolved","Single lab, limited mechanistic follow-up"]},{"year":2025,"claim":"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","pmids":["40100474"],"confidence":"Medium","gaps":["m6A-GPX4 axis not reconstituted in vitro","Relationship to canonical t6A enzymatic role unclear","Single lab"]},{"year":2024,"claim":"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","pmids":["38456959"],"confidence":"Low","gaps":["Biochemical link between OSGEP and MEK/ERK not defined","Single lab; not independently confirmed"]},{"year":2025,"claim":"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","pmids":["40796998"],"confidence":"Low","gaps":["Not independently replicated","No mutagenesis/reconstitution controls described","Contradicts the established and well-supported t6A enzyme function"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[7]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,4]}],"complexes":["KEOPS/EKC complex"],"partners":["BUD32","HNRNPUL1","YTHDC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPF4","full_name":"tRNA N6-adenosine threonylcarbamoyltransferase","aliases":["N6-L-threonylcarbamoyladenine synthase","t(6)A synthase","O-sialoglycoprotein endopeptidase","hOSGEP","t(6)A37 threonylcarbamoyladenosine biosynthesis protein OSGEP","tRNA threonylcarbamoyladenosine biosynthesis protein OSGEP"],"length_aa":335,"mass_kda":36.4,"function":"Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37. OSGEP likely plays a direct catalytic role in this reaction, but requires other protein(s) of the complex to fulfill this activity","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NPF4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/OSGEP","classification":"Common Essential","n_dependent_lines":1184,"n_total_lines":1208,"dependency_fraction":0.9801324503311258},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OSGEP","total_profiled":1310},"omim":[{"mim_id":"619634","title":"O-SIALOGLYCOPROTEIN ENDOPEPTIDASE-LIKE 1; OSGEPL1","url":"https://www.omim.org/entry/619634"},{"mim_id":"617731","title":"GALLOWAY-MOWAT SYNDROME 5; GAMOS5","url":"https://www.omim.org/entry/617731"},{"mim_id":"617730","title":"GALLOWAY-MOWAT SYNDROME 4; GAMOS4","url":"https://www.omim.org/entry/617730"},{"mim_id":"617729","title":"GALLOWAY-MOWAT SYNDROME 3; GAMOS3","url":"https://www.omim.org/entry/617729"},{"mim_id":"617436","title":"GON7 SUBUNIT OF KEOPS COMPLEX; GON7","url":"https://www.omim.org/entry/617436"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OSGEP"},"hgnc":{"alias_symbol":["PRSMG1","GCPL1","OSGEP1","KAE1","TCS3"],"prev_symbol":[]},"alphafold":{"accession":"Q9NPF4","domains":[{"cath_id":"3.30.420.40","chopping":"2-113_290-327","consensus_level":"medium","plddt":96.7277,"start":2,"end":327},{"cath_id":"3.30.420.40","chopping":"125-285","consensus_level":"medium","plddt":96.4346,"start":125,"end":285}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPF4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPF4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPF4-F1-predicted_aligned_error_v6.png","plddt_mean":96.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OSGEP","jax_strain_url":"https://www.jax.org/strain/search?query=OSGEP"},"sequence":{"accession":"Q9NPF4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPF4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPF4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPF4"}},"corpus_meta":[{"pmid":"21285948","id":"PMC_21285948","title":"A role for the universal Kae1/Qri7/YgjD (COG0533) family in tRNA modification.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21285948","citation_count":138,"is_preprint":false},{"pmid":"14996906","id":"PMC_14996906","title":"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).","date":"2004","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/14996906","citation_count":94,"is_preprint":false},{"pmid":"28272532","id":"PMC_28272532","title":"tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy.","date":"2017","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/28272532","citation_count":74,"is_preprint":false},{"pmid":"11934690","id":"PMC_11934690","title":"Impaired trafficking of distal renal tubular acidosis mutants of the human kidney anion exchanger kAE1.","date":"2002","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11934690","citation_count":72,"is_preprint":false},{"pmid":"17766251","id":"PMC_17766251","title":"An archaeal orthologue of the universal protein Kae1 is an iron metalloprotein which exhibits atypical DNA-binding properties and apurinic-endonuclease activity in vitro.","date":"2007","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17766251","citation_count":63,"is_preprint":false},{"pmid":"12227829","id":"PMC_12227829","title":"Impaired trafficking of human kidney anion exchanger (kAE1) caused by hetero-oligomer formation with a truncated mutant associated with distal renal tubular acidosis.","date":"2002","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12227829","citation_count":58,"is_preprint":false},{"pmid":"19172740","id":"PMC_19172740","title":"Structure of the archaeal Kae1/Bud32 fusion protein MJ1130: a model for the eukaryotic EKC/KEOPS 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Eukarya.","date":"2009","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/19143597","citation_count":32,"is_preprint":false},{"pmid":"12039036","id":"PMC_12039036","title":"Sequencing analysis of a putative human O-sialoglycoprotein endopeptidase gene (OSGEP) and analysis of a bidirectional promoter between the OSGEP and APEX genes.","date":"2002","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12039036","citation_count":24,"is_preprint":false},{"pmid":"30558655","id":"PMC_30558655","title":"Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype.","date":"2018","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30558655","citation_count":22,"is_preprint":false},{"pmid":"17553790","id":"PMC_17553790","title":"Interaction of integrin-linked kinase with the kidney chloride/bicarbonate exchanger, kAE1.","date":"2007","source":"The Journal of biological 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(Apexp1).","date":"1999","source":"Acta medica Okayama","url":"https://pubmed.ncbi.nlm.nih.gov/10631378","citation_count":4,"is_preprint":false},{"pmid":"36416748","id":"PMC_36416748","title":"Kae1 of Saccharomyces cerevisiae KEOPS complex possesses ADP/GDP nucleotidase activity.","date":"2022","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/36416748","citation_count":3,"is_preprint":false},{"pmid":"40100474","id":"PMC_40100474","title":"OSGEP, A Negative Ferroptotic Regulator, Alleviates Cerebral Ischemia-Reperfusion Injury Through Modulating m6A Methylation of GPX4 mRNA.","date":"2025","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/40100474","citation_count":3,"is_preprint":false},{"pmid":"29567474","id":"PMC_29567474","title":"Treacher Collins syndrome 3 (TCS3)-associated POLR1C mutants are localized in the lysosome and inhibits chondrogenic differentiation.","date":"2018","source":"Biochemical and biophysical research 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of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/39661309","citation_count":2,"is_preprint":false},{"pmid":"38669699","id":"PMC_38669699","title":"Unraveling the molecular landscape of kAE1: a narrative review.","date":"2024","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38669699","citation_count":1,"is_preprint":false},{"pmid":"29651904","id":"PMC_29651904","title":"Adaptor protein 1 B mu subunit does not contribute to the recycling of kAE1 protein in polarized renal epithelial cells.","date":"2018","source":"Molecular membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/29651904","citation_count":1,"is_preprint":false},{"pmid":"40796998","id":"PMC_40796998","title":"Identification and characterisation of subtype-specific anti-N-CoR OSGEP protease in acute myeloid leukaemia (AML-M5) cell lineage.","date":"2025","source":"Biotechnology 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\"finding\": \"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.\",\n      \"method\": \"Yeast mutant analysis, comparative genomics, structural analysis, functional complementation, tRNA modification assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical phenotype (t6A loss) in null mutants, replicated with multiple genetic and biochemical approaches, foundational paper widely cited\",\n      \"pmids\": [\"21285948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Protein purification, in vitro biochemical assays (DNA binding, AP-endonuclease assay), EPR, metal analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro reconstitution with purified archaeal ortholog, but single lab, and this is the archaeal ortholog not mammalian OSGEP\",\n      \"pmids\": [\"17766251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, in vitro kinase assay, site-directed mutagenesis, yeast genetic studies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with in vitro kinase assay and mutagenesis with in vivo functional validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19172740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation/localization (fluorescence microscopy), genetic complementation, mitochondrial genome maintenance assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence in two model organisms, but study concerns the mitochondrial paralog (OSGEPL) not cytoplasmic OSGEP\",\n      \"pmids\": [\"19578062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Exome sequencing, yeast complementation, LC-MS/MS quantification of t6A levels\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct biochemical quantification of t6A by LC-MS/MS combined with genetic complementation in yeast, multiple orthogonal methods in single study\",\n      \"pmids\": [\"28272532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Drosophila genetic allelic series, tRNA modification analysis, yeast complementation, clonal analysis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — extensive allelic series in Drosophila with direct t6A quantification and yeast complementation; tissue-specific phenotype established by clonal analysis; multiple orthogonal methods\",\n      \"pmids\": [\"26516084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"QTL mapping, reciprocal hemizygous analysis, TORC1 activation assay, fermentation kinetics measurement\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal hemizygous validation with phenotypic readouts in two separate assays, single lab\",\n      \"pmids\": [\"31417508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein purification, in vitro nucleotidase/ATPase/GTPase assays, site-directed mutagenesis, yeast telomere length assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with purified recombinant complexes and mutagenesis, functional in vivo validation of telomere phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36416748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mice, transcriptomics, proteomics, insulin secretion assays, UPR pathway analysis, overexpression rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vivo approaches (global KO, conditional KO, OE rescue) with mechanistic pathway placement linking t6A modification to translational fidelity and UPR\",\n      \"pmids\": [\"39622811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Patient-derived lymphoblastoid cell lines, confocal microscopy with tagged mutant proteins, western blot, DDR signaling analysis\",\n      \"journal\": \"Clinica chimica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — direct localization experiment with functional consequence (DDR activation), single lab, limited mechanistic follow-up beyond localization\",\n      \"pmids\": [\"34666032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"MCAO mouse model, OGD/R neuronal cultures, gain- and loss-of-function experiments, m6A methylation analysis, RNA immunoprecipitation, co-immunoprecipitation\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — multiple in vivo/in vitro methods but single lab, mechanistic pathway (m6A-GPX4) supported by RIP and co-IP but not fully reconstituted\",\n      \"pmids\": [\"40100474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse HIRI model, OGD/R cell model, gain- and loss-of-function, ERK1/2 rescue experiments, ALT/AST measurements\",\n      \"journal\": \"Molecular biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological/genetic rescue establishes pathway placement but mechanism linking OSGEP to MEK/ERK is not biochemically defined\",\n      \"pmids\": [\"38456959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA/genomic cloning, sequencing, luciferase promoter assay in HeLa cells, Northern blot\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional promoter mapping by reporter assay, single lab, no direct protein functional characterization\",\n      \"pmids\": [\"12039036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"HPLC size exclusion chromatography, mass spectrometry, in vitro protease assay with recombinant N-CoR, transfection studies across cell lines\",\n      \"journal\": \"Biotechnology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, novel protease claim for mammalian OSGEP that contradicts the established t6A enzyme function; not independently replicated; abstract does not describe rigorous mutagenesis or reconstitution controls\",\n      \"pmids\": [\"40796998\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OSGEP (KAE1) is the catalytic subunit of the evolutionarily conserved KEOPS complex responsible for biosynthesis of N6-threonylcarbamoyl adenosine (t6A) at position 37 of tRNAs decoding ANN codons, a modification essential for translational fidelity; structurally, it adopts an ASKHA fold, binds iron, carries ADP/GDP nucleotidase activity contributing to telomere maintenance, and physically interacts with and inhibits the kinase activity of the Bud32/PRPK subunit; loss of OSGEP impairs proinsulin translation and activates the unfolded protein response in pancreatic β-cells, and pathogenic OSGEP variants cause Galloway-Mowat syndrome by reducing t6A levels and disrupting global protein synthesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #5]. 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 [#2]. 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 [#7]. The t6A function has direct physiological consequences for translational fidelity: in pancreatic \\u03b2-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 [#8]. Pathogenic OSGEP variants cause Galloway-Mowat syndrome by reducing t6A levels and disrupting global protein synthesis [#4], and patient-derived variants additionally reduce OSGEP protein, mislocalize it to the cytosol, and activate the DNA damage response [#9]. Reported ferroptosis-suppressing and N-CoR protease activities of mammalian OSGEP have not been corroborated beyond single low-confidence studies in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Protein purification and in vitro DNA-binding/AP-endonuclease assays, EPR and metal analysis of purified archaeal Kae1\",\n      \"pmids\": [\"17766251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Studied the archaeal ortholog, not mammalian OSGEP\", \"In vitro DNA activities not connected to the later-established t6A function\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that mitochondrial paralogs (Qri7/OSGEPL) localize to mitochondria and maintain the mitochondrial genome, distinguishing a paralogous mitochondrial branch from cytoplasmic OSGEP.\",\n      \"evidence\": \"Fluorescence localization, genetic complementation and mitochondrial genome maintenance assays in yeast and C. elegans\",\n      \"pmids\": [\"19578062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Concerns the mitochondrial paralog OSGEPL, not cytoplasmic OSGEP\", \"Does not address t6A biosynthesis directly\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography of an archaeal Kae1/Bud32 fusion, in vitro kinase assay, mutagenesis and yeast genetics\",\n      \"pmids\": [\"19172740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which kinase repression couples to t6A synthesis not resolved\", \"Telomere function mechanism left undefined at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast null mutant analysis, comparative genomics, structural analysis and tRNA modification assays\",\n      \"pmids\": [\"21285948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism of t6A transfer within the complex not fully dissected\", \"Did not establish mammalian disease relevance\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed conservation of the t6A function in a metazoan and revealed differential tissue sensitivity, with proliferating tissues most vulnerable to t6A loss.\",\n      \"evidence\": \"Drosophila allelic series, tRNA modification quantification, yeast complementation and clonal analysis\",\n      \"pmids\": [\"26516084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of proliferative-tissue sensitivity not defined\", \"No mammalian in vivo confirmation in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Exome sequencing, yeast complementation and LC-MS/MS quantification of t6A\",\n      \"pmids\": [\"28272532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific basis of the renal/neurological phenotype not explained\", \"Effects on specific tRNAs not enumerated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked t6A status to nutrient signaling by validating KAE1 as a determinant of TORC1 activation by glutamine and of fermentation under low nitrogen.\",\n      \"evidence\": \"QTL mapping, reciprocal hemizygous analysis, TORC1 activation and fermentation assays in yeast\",\n      \"pmids\": [\"31417508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting t6A to TORC1 not defined\", \"Yeast-specific; not confirmed in mammalian cells\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Recombinant complex reconstitution, in vitro nucleotidase assays, mutagenesis and yeast telomere assays\",\n      \"pmids\": [\"36416748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nucleotidase activity mechanistically influences telomeres unknown\", \"Demonstrated in yeast complex; mammalian relevance untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed OSGEP t6A function in a mammalian physiological pathway by showing \\u03b2-cell OSGEP loss impairs proinsulin translational fidelity, triggers UPR and apoptosis, and causes hyperglycemia, with overexpression rescuing insulin secretion.\",\n      \"evidence\": \"Global and \\u03b2-cell-specific knockout mice, transcriptomics/proteomics, insulin secretion and UPR assays, overexpression rescue\",\n      \"pmids\": [\"39622811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific mistranslated codons in proinsulin not enumerated\", \"Whether non-\\u03b2-cell tissues share this UPR axis untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Characterized human disease variants at the cellular level, showing reduced OSGEP protein, cytosolic mislocalization/aggregation, and DNA damage response activation.\",\n      \"evidence\": \"Patient lymphoblastoid lines, confocal microscopy of tagged mutants, western blot and DDR analysis\",\n      \"pmids\": [\"34666032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DDR activation is a direct OSGEP function or downstream of t6A loss unresolved\", \"Single lab, limited mechanistic follow-up\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"MCAO/OGD-R models, gain/loss-of-function, m6A analysis, RIP and co-IP\",\n      \"pmids\": [\"40100474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A-GPX4 axis not reconstituted in vitro\", \"Relationship to canonical t6A enzymatic role unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reported that OSGEP overexpression protects against hepatic ischemia-reperfusion ferroptosis through MEK/ERK signaling.\",\n      \"evidence\": \"Mouse HIRI and OGD/R cell models with ERK1/2 rescue experiments\",\n      \"pmids\": [\"38456959\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Biochemical link between OSGEP and MEK/ERK not defined\", \"Single lab; not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"HPLC isolation, mass spectrometry, in vitro protease assay and transfection studies\",\n      \"pmids\": [\"40796998\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Not independently replicated\", \"No mutagenesis/reconstitution controls described\", \"Contradicts the established and well-supported t6A enzyme function\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 4]}\n    ],\n    \"complexes\": [\"KEOPS/EKC complex\"],\n    \"partners\": [\"BUD32\", \"HNRNPUL1\", \"YTHDC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}