OSGEP

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.

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

• 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