{"gene":"NAA10","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2014,"finding":"The Ogden syndrome NAA10 p.Ser37Pro (S37P) mutant shows reduced in vitro catalytic activity and reduced subunit complexation with NAA15 in immunoprecipitation experiments. In a yeast complementation model, wild-type human NatA fully rescued NatA-deletion yeast phenotypes whereas the S37P mutant only partially rescued, and quantitative Nt-acetylome analysis showed globally reduced N-terminal acetylation of NatA substrates in yeast expressing the mutant compared to wild-type hNatA.","method":"Yeast complementation (genetic epistasis), immunoprecipitation, in vitro N-terminal acetylation assay, quantitative Nt-acetylome proteomics","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (in vitro assay, Co-IP, quantitative proteomics, genetic complementation) in a single rigorous study","pmids":["24408909"],"is_preprint":false},{"year":2016,"finding":"Recombinant Naa10/ARD1 does not acetylate lysine residues of reported substrates (MSRA, MLCK, RUNX2) above background levels in vitro, suggesting previously reported lysine acetylation events are chemical rather than enzymatic; no difference was detected with or without Naa10 in the reaction.","method":"In vitro reconstitution acetylation assay with recombinant proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro reconstitution with purified recombinant proteins, explicitly negative result replicated across multiple proposed substrates in a single focused study","pmids":["26755727"],"is_preprint":false},{"year":2014,"finding":"NAA10 is the catalytic subunit of the NatA complex (with auxiliary subunit NAA15); in vitro N-terminal acetylation assays showed that disease-associated missense variants (including p.Ser37Pro) have reduced catalytic activity, and phenotypic severity correlates with the degree of residual NatA catalytic activity.","method":"In vitro N-terminal acetylation assays","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay replicated across multiple variants, single lab","pmids":["25099252"],"is_preprint":false},{"year":2015,"finding":"Zebrafish Naa10 (zNaa10) possesses N-terminal acetyltransferase activity with substrate specificity highly similar to human NAA10, as demonstrated by in vitro NAT assays; morpholino-mediated knockdown of naa10 in zebrafish caused increased lethality, growth retardation, bent axis, abnormal eyes and bent tails, establishing an essential developmental role.","method":"In vitro N-terminal acetylation assay; morpholino knockdown in zebrafish with phenotypic readout","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzymatic assay plus in vivo loss-of-function with defined developmental phenotypes, single lab","pmids":["26251455"],"is_preprint":false},{"year":2015,"finding":"The NAA10 p.Tyr43Ser mutant shows significantly decreased catalytic activity and reduced protein stability compared to wild-type in in vitro assays, demonstrating that the Tyr43 residue is important for both enzymatic activity and stability.","method":"In vitro N-terminal acetylation assay; protein stability assessment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic and stability assay, single lab, single study","pmids":["26522270"],"is_preprint":false},{"year":2016,"finding":"In vitro enzymatic assays for NAA10 missense variants p.Arg83Cys and p.Phe128Leu revealed reduced catalytic N-terminal acetyltransferase activity, linking these variants to pathogenicity.","method":"In vitro N-terminal acetylation assay","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay for multiple variants, single lab","pmids":["27094817"],"is_preprint":false},{"year":2019,"finding":"Biochemical analyses of NAA10 and NAA15 variants as part of the human NatA complex, including with and without the HYPK regulatory subunit, showed variant-specific impairment of N-terminal acetyltransferase activity, with HYPK modulating NatA enzymatic activity.","method":"In vitro N-terminal acetylation assay with reconstituted NatA complex ± HYPK","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstituted complex enzymatic assays with regulatory subunit, single lab, multiple variants","pmids":["31127942"],"is_preprint":false},{"year":2018,"finding":"NAA10 p.Ile72Thr variant is protein-destabilized and has decreased monomeric NAT activity, but NatA complex activity (with NAA15) appears normal; binding to NAA15 is most likely intact, suggesting distinct roles for monomeric NAA10 vs. NatA complex activity.","method":"In vitro acetylation assay (monomeric and NatA complex); protein stability studies","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — two orthogonal functional assays (enzymatic, stability), single lab","pmids":["29748569"],"is_preprint":false},{"year":2018,"finding":"NAA10 p.V111G has reduced monomeric catalytic activity and reduced protein stability, but NatA complex activity is unaltered, as shown by cycloheximide chase and in vitro acetylation assays; this represents isolated monomeric NAA10 dysfunction without NatA impairment.","method":"In vitro N-terminal acetylation assay (monomeric vs. NatA complex); cycloheximide chase","journal":"BMC medical genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — two orthogonal functional methods, single lab","pmids":["29558889"],"is_preprint":false},{"year":2019,"finding":"NAA10 p.R83H has reduced monomeric catalytic acetyltransferase activity, likely due to impaired enzyme-Ac-CoA binding, as modeled by the altered charge density in the Ac-CoA binding region; NatA complex activity was not separately assessed.","method":"In vitro N-terminal acetylation assay (monomeric NAA10); structural modeling","journal":"BMC medical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro assay plus computational modeling, single lab","pmids":["31174490"],"is_preprint":false},{"year":2020,"finding":"NAA10 p.His16Pro impairs NatA complex formation and NatA catalytic activity, while monomeric NAA10 catalytic activity and cellular protein stability are unaffected, as shown by immunoprecipitation and in vitro acetylation assays; cycloheximide chase confirmed normal stability.","method":"Immunoprecipitation (NatA complex formation); in vitro N-terminal acetylation assay; cycloheximide chase","journal":"BMC medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus enzymatic assay plus stability assay, multiple orthogonal methods, single lab","pmids":["32698785"],"is_preprint":false},{"year":2020,"finding":"NAA10 p.D10G and p.L11R variants both impair complex formation with NAA15 (shown by immunoprecipitation), but have opposing effects on catalytic activity: D10G retains normal NatA activity but reduced monomeric NAT activity, while L11R shows reduced NatA activity but normal monomeric NAT activity.","method":"Immunoprecipitation; in vitro N-terminal acetylation assay (monomeric and NatA complex)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus enzymatic assays, single lab, two orthogonal methods","pmids":["33255974"],"is_preprint":false},{"year":2020,"finding":"Monomeric recombinant hARD1/NAA10 exhibits lysine acetyltransferase (KAT) activity in vitro, but this activity is lost as the protein forms oligomers over time; size-exclusion analysis showed oligomeric NAA10 lacks KAT activity while the monomeric form retains it, with activity dependent on reactant concentrations and reaction time.","method":"In vitro lysine acetylation assay; size-exclusion chromatography","journal":"Molecules (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 1 / Weak — single lab, in vitro assay only; contradicted by Magin et al. 2016 (PMID 26755727) which found no KAT activity; conflicting data lowers confidence","pmids":["32013195"],"is_preprint":false},{"year":2021,"finding":"NAA10 Trp38 hydroxylation by FIH (factor inhibiting HIF-1α) could not be detected in multiple human cell lines, and no interaction between NAA10 and FIH was found, indicating that Trp38 hydroxylation is not a regulatory switch converting NAA10 from NAT to KAT activity in human cells.","method":"Mass spectrometry (hydroxylation detection); Co-IP (NAA10-FIH interaction); cell fractionation in multiple human cell lines","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MS, Co-IP) across multiple cell lines, explicitly negative finding, single lab","pmids":["34769235"],"is_preprint":false},{"year":2021,"finding":"Naa12, a previously unannotated Naa10 paralog with NAT activity, genetically compensates for Naa10 in mice; Naa10 single-knockout male mice do not show globally apparent amino-terminal acetylation impairment, but Naa10/Naa12 double-knockout mice are embryonic lethal, establishing Naa12 as a functional redundant enzyme.","method":"Mouse knockout genetics (single and double knockout); phenotypic analysis; enzymatic activity assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-knockout genetic epistasis with embryonic lethality, enzymatic activity characterization, replicated in multiple alleles in same study","pmids":["34355692"],"is_preprint":false},{"year":2022,"finding":"Biochemical characterization of novel NAA10 variants (p.A6P, p.R79C, p.Q129P, p.E157K) by in vitro acetylation assays revealed distinct impacts on N-terminal acetyltransferase activity, with some variants specifically impairing monomeric NAA10 activity while others impair NatA complex activity, suggesting multiple distinct pathogenic mechanisms.","method":"In vitro N-terminal acetylation assay (monomeric and NatA complex)","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic in vitro enzymatic characterization of multiple variants, single lab","pmids":["35039925"],"is_preprint":false},{"year":2019,"finding":"Naa10 deficiency in mouse embryonic stem cells augments FGF/MAPK signaling and attenuates differentiation towards the epiblast lineage (deviating towards primitive endoderm), demonstrating a role for Naa10-mediated N-terminal acetylation in regulating FGF/MAPK pathway activity and epiblast specification.","method":"Naa10 knockout mESCs; differentiation assays; pathway analysis","journal":"In vitro cellular & developmental biology. Animal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined cellular phenotype with pathway placement (FGF/MAPK), single lab, single study","pmids":["30993557"],"is_preprint":false},{"year":2018,"finding":"siRNA screen identified NAA10 as a factor in the transcriptional machinery regulating PXR (pregnane X receptor) transcription in pancreatic cancer cells; NAA10 knockdown reduced PXR transcript levels.","method":"siRNA library screen; deconvolution validation; qRT-PCR","journal":"Biochemical pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA screen with limited mechanistic follow-up, single lab","pmids":["30566892"],"is_preprint":false},{"year":2016,"finding":"Stable knockdown of Naa10 in H1299 cells caused morphological changes and, by cDNA microarray, upregulation of netrin-1 (NTN1) and its receptor UNC5B as early downstream targets; this relationship was validated in mouse embryos and upon all-trans retinoic acid treatment, indicating Naa10 negatively regulates NTN1/UNC5B expression.","method":"Stable shRNA knockdown; cDNA microarray; validation in mouse embryo tissue; retinoic acid treatment","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, transcriptomic downstream target identification with limited mechanistic follow-up","pmids":["27910960"],"is_preprint":false},{"year":2024,"finding":"RGMB-AS1 lncRNA binds to the 82–87 amino acid region of NAA10, stimulating its acetyltransferase activity and promoting the conversion of acetyl-CoA to HMG-CoA, contributing to ferroptosis in NSCLC; this was demonstrated by co-IP and functional assays.","method":"Co-immunoprecipitation; in vitro acetyltransferase activity assay; cell and xenograft functional assays","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP with functional assay; lncRNA-protein interaction claim with limited mechanistic detail in abstract","pmids":["38574881"],"is_preprint":false},{"year":2026,"finding":"NAA10 promotes acetylation of CREBRF, which facilitates BTRC (an E3 ubiquitin ligase)-mediated ubiquitination and degradation of CREBRF, thereby activating endoplasmic reticulum stress and exacerbating renal tubular injury in diabetic kidney disease; interactions confirmed by Co-IP.","method":"Co-immunoprecipitation; ubiquitination/acetylation assays; knockdown/overexpression in HK-2 cells and STZ mouse model","journal":"Journal of diabetes investigation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP with functional rescue; lysine acetylation by NAA10 remains controversial (see PMID 26755727)","pmids":["42262012"],"is_preprint":false},{"year":2026,"finding":"UBE2M promotes neddylation of NAA10 at K148, mediated by the RBX1-CUL4A E3 ligase complex, which enhances NAA10 protein stability and functional activity; knockdown of NAA10 suppressed UBE2M-driven prostate cancer cell proliferation, placing NAA10 downstream of the UBE2M neddylation pathway.","method":"Co-immunoprecipitation; mass spectrometry; proximity ligation assay; site-directed mutagenesis (K148); knockdown/overexpression in PCa cells and xenografts","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, MS, PLA (three orthogonal methods), mutagenesis at neddylation site, single lab","pmids":["41857595"],"is_preprint":false},{"year":2026,"finding":"NAA10 acetylates C7orf50 at lysine-71/72/76 residues; this acetylation, regulated by mTOR (which phosphorylates NAA10 as a nutritional status-responsive acetyltransferase), determines C7orf50 nucleolar localization and coordinates ribosome biogenesis vs. autophagy in response to nutrient status.","method":"In vitro and in vivo acetylation assays; site-directed mutagenesis; localization imaging; mTOR pathway perturbation","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro and in vivo acetylation assays with mutagenesis of target lysines, single lab; KAT activity of NAA10 remains controversial but here supported by mutagenesis","pmids":["42139339"],"is_preprint":false},{"year":2026,"finding":"NME3 interacts with NAA10 in human dental pulp stem cells (identified by mass spectrometry and confirmed by colocalization); NAA10 knockdown rescued odontogenic differentiation deficits caused by NME3 silencing, and NAA10 overexpression attenuated NME3 effects, placing NAA10 as a downstream effector of NME3 in regulating RUNX2 nuclear translocation.","method":"Mass spectrometry; colocalization imaging; knockdown rescue assay; overexpression assay","journal":"FASEB journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction by MS and colocalization, functional epistasis by KD rescue, single lab, single study","pmids":["42165278"],"is_preprint":false},{"year":2024,"finding":"Computational structural analysis of NAA10 F128I and F128L disease-associated mutations revealed that F128I reduces flexibility of the substrate-binding region (impairing substrate peptide binding), while F128L reduces flexibility of the Ac-CoA binding region, demonstrating two mechanistically distinct paths to catalytic inactivation.","method":"Molecular dynamics simulation; structural modeling; conformational plasticity analysis","journal":"Computational and structural biotechnology journal","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no in vitro or in vivo experimental validation reported","pmids":["39610905"],"is_preprint":false},{"year":2014,"finding":"Patient fibroblasts from males with the NAA10 c.471+2T→A splice donor mutation lacked full-length NAA10 protein and showed cell proliferation defects; retinol uptake was decreased in patient cells, and expression arrays showed significant dysregulation of genes in the retinoic acid signalling pathway including BMP4, STRA6, and downstream targets of BCOR and canonical WNT.","method":"Protein expression (Western blot); cell proliferation assay; retinol uptake assay; expression array","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in patient-derived cells, single lab","pmids":["24431331"],"is_preprint":false},{"year":2021,"finding":"Down-regulation of NAA10 in rat OGD/R and MCAO models reversed the attenuation of ERK1/2 phosphorylation normally induced by sevoflurane preconditioning, indicating NAA10 mediates neuroprotective effects through regulation of ERK1/2 phosphorylation.","method":"siRNA knockdown in vitro (OGD/R) and in vivo (MCAO); Western blot for phospho-ERK1/2; TTC staining; TUNEL assay","journal":"Neuroscience letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement via KD with phosphorylation readout, limited mechanistic detail","pmids":["33872734"],"is_preprint":false},{"year":2026,"finding":"In a NAA10 knockout (ΔNAA10) glioblastoma cell line generated by CRISPR/Cas9, patient variants p.L126R and p.F128L severely impaired NatA complex formation and altered cellular distribution of NAA10, while p.L126V maintained near-wild-type protein stability and colocalization with NAA15, demonstrating that clinical severity is driven by the specific amino acid substitution's effect on NatA complex assembly.","method":"CRISPR/Cas9 NAA10 knockout cell line; GFP-tagged variant re-expression; colocalization imaging with NAA15","journal":"Molecular and cellular pediatrics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR null background with variant re-expression and colocalization, orthogonal to prior Co-IP data, single lab","pmids":["41973310"],"is_preprint":false}],"current_model":"NAA10 is the catalytic subunit of the NatA N-terminal acetyltransferase complex (with auxiliary subunit NAA15 and regulatory subunit HYPK), responsible for co-translational N-terminal acetylation of ~40–50% of the human proteome; disease-associated missense variants impair either monomeric NAA10 catalytic activity, NatA complex formation/activity, or protein stability—through distinct biochemical mechanisms—and a paralogous enzyme Naa12 can genetically compensate for Naa10 loss in mice; additionally, NAA10 undergoes neddylation (at K148 by the RBX1-CUL4A/UBE2M machinery), participates in regulating FGF/MAPK signaling and retinoic acid pathway gene expression, and has been proposed (though controversially) to also acetylate internal lysine residues of select substrates."},"narrative":{"mechanistic_narrative":"NAA10 is the catalytic subunit of the NatA N-terminal acetyltransferase complex, which it forms with the auxiliary subunit NAA15 to co-translationally acetylate the N-termini of NatA-class substrates [PMID:24408909, PMID:25099252]. Its N-terminal acetyltransferase activity and substrate specificity are conserved from zebrafish to human, and loss of function produces essential developmental phenotypes including growth retardation and axis/eye defects [PMID:26251455]. NAA10 catalytic activity exists in two functionally separable forms — monomeric NAA10 NAT activity and NAA15-dependent NatA complex activity — and disease-associated missense variants impair these through distinct biochemical mechanisms: reduced monomeric catalysis, impaired NatA complex assembly, or decreased protein stability [PMID:29748569, PMID:29558889, PMID:32698785, PMID:33255974, PMID:35039925]. The severity of NAA10-related (Ogden) syndrome tracks with the degree to which a given substitution disrupts NatA complex formation and residual catalytic activity [PMID:24408909, PMID:25099252, PMID:41973310]. In mice, the loss of Naa10 is genetically buffered by the paralog Naa12, which retains NAT activity, such that single Naa10 knockout shows no global acetylation defect whereas Naa10/Naa12 double knockout is embryonic lethal [PMID:34355692]. Beyond its catalytic role, NAA10 is stabilized and activated by neddylation at K148 via the RBX1-CUL4A/UBE2M machinery [PMID:41857595], and NatA-dependent activity feeds into developmental signaling, modulating FGF/MAPK output and epiblast specification [PMID:30993557] and retinoic-acid pathway gene expression [PMID:24431331]. Whether NAA10 acts as a genuine lysine (internal) acetyltransferase is contested: recombinant NAA10 failed to acetylate proposed lysine substrates above background [PMID:26755727], and Trp38 hydroxylation by FIH proposed to switch NAA10 to a KAT was not detectable in human cells [PMID:34769235].","teleology":[{"year":2014,"claim":"Established NAA10 as the catalytic subunit of NatA and showed that the Ogden syndrome S37P substitution causes disease by reducing both catalysis and NAA15 complexation, defining a loss-of-function mechanism.","evidence":"Yeast complementation, immunoprecipitation, in vitro NAT assay, and quantitative Nt-acetylome proteomics; parallel in vitro NAT assays across variants","pmids":["24408909","25099252"],"confidence":"High","gaps":["Did not separate monomeric NAA10 dysfunction from NatA complex dysfunction","Substrate-level consequences in human cells not mapped"]},{"year":2014,"claim":"Linked NAA10 loss to a defined human cellular phenotype, showing protein loss disrupts proliferation and dysregulates retinoic-acid pathway gene expression.","evidence":"Patient fibroblasts with splice-donor mutation; Western blot, proliferation, retinol uptake, and expression arrays","pmids":["24431331"],"confidence":"Medium","gaps":["Direct acetylation substrates linking NAA10 to retinoic-acid genes not identified","Causality vs. correlation of transcriptional changes unresolved"]},{"year":2015,"claim":"Demonstrated conservation of NAA10 NAT activity and substrate specificity and an essential developmental requirement in a vertebrate model.","evidence":"In vitro NAT assay of zebrafish Naa10; morpholino knockdown with developmental phenotyping","pmids":["26251455"],"confidence":"Medium","gaps":["Morpholino off-target effects not fully excluded","Specific substrates underlying developmental phenotypes unknown"]},{"year":2016,"claim":"Challenged the proposed lysine-acetyltransferase function by showing recombinant NAA10 does not acetylate reported KAT substrates above background.","evidence":"In vitro reconstitution acetylation assays with purified recombinant proteins across multiple substrates (MSRA, MLCK, RUNX2)","pmids":["26755727"],"confidence":"High","gaps":["Cannot exclude KAT activity requiring cofactors or partners absent in vitro","Does not address context-specific KAT activity in cells"]},{"year":2018,"claim":"Resolved that monomeric NAA10 catalysis and NatA complex catalysis are functionally separable, with variants able to impair one while sparing the other.","evidence":"In vitro NAT assays of monomeric vs. NatA complex plus cycloheximide chase for p.I72T and p.V111G","pmids":["29748569","29558889"],"confidence":"Medium","gaps":["Physiological role of monomeric NAA10 activity distinct from NatA not defined","In vivo substrates of monomeric form unknown"]},{"year":2019,"claim":"Showed HYPK modulates reconstituted NatA enzymatic activity and that variants impair complex activity in a subunit-context-dependent manner.","evidence":"In vitro NAT assays with reconstituted NatA ±HYPK across variants; additional monomeric assays with Ac-CoA-binding structural modeling","pmids":["31127942","31174490"],"confidence":"Medium","gaps":["HYPK regulatory mechanism at residue level not resolved","Cellular relevance of HYPK modulation not tested"]},{"year":2019,"claim":"Placed NAA10-mediated acetylation upstream of developmental signaling, showing Naa10 loss augments FGF/MAPK and biases lineage choice.","evidence":"Naa10 knockout mESC differentiation and pathway analysis","pmids":["30993557"],"confidence":"Medium","gaps":["Direct NAA10 substrate in the FGF/MAPK axis not identified","Single cellular system"]},{"year":2020,"claim":"Defined distinct pathogenic mechanisms at the assembly level, with variants selectively disrupting NatA complex formation, monomeric catalysis, or stability, sometimes in opposing directions.","evidence":"Immunoprecipitation and in vitro NAT assays (monomeric and complex) plus cycloheximide chase for p.H16P, p.D10G, p.L11R","pmids":["32698785","33255974"],"confidence":"Medium","gaps":["Genotype-phenotype correlation for opposing biochemical effects not clinically resolved","Single-lab biochemistry"]},{"year":2021,"claim":"Revealed genetic redundancy by identifying the paralog Naa12, explaining the mild single-knockout phenotype and establishing combined NAT activity as essential for viability.","evidence":"Mouse single and double knockout genetics with enzymatic activity assays","pmids":["34355692"],"confidence":"High","gaps":["Relative substrate division between Naa10 and Naa12 in vivo not mapped","Tissue-specific dependence unclear"]},{"year":2021,"claim":"Tested and rejected a proposed NAT-to-KAT regulatory switch, finding no NAA10 Trp38 hydroxylation or FIH interaction in human cells.","evidence":"Mass spectrometry, Co-IP, and cell fractionation across multiple human cell lines (negative result)","pmids":["34769235"],"confidence":"Medium","gaps":["Cannot exclude transient or condition-specific hydroxylation","Does not resolve KAT activity question broadly"]},{"year":2026,"claim":"Identified neddylation at K148 by RBX1-CUL4A/UBE2M as a post-translational input that stabilizes and activates NAA10, integrating it into the neddylation signaling pathway.","evidence":"Co-IP, mass spectrometry, proximity ligation, K148 mutagenesis, and knockdown in prostate cancer cells and xenografts","pmids":["41857595"],"confidence":"Medium","gaps":["Downstream NAA10 substrates mediating proliferation not identified","Generality beyond cancer context untested"]},{"year":2026,"claim":"Reopened the lysine-acetyltransferase model with mutagenesis-supported claims that NAA10 acetylates specific lysines on C7orf50 (nutrient/mTOR-responsive) and CREBRF, despite continued controversy over KAT activity.","evidence":"In vitro and in vivo acetylation assays with target-lysine mutagenesis, localization imaging, mTOR perturbation; separate Co-IP and ubiquitination/acetylation assays","pmids":["42139339","42262012"],"confidence":"Medium","gaps":["Conflicts with prior negative reconstitution data (PMID 26755727)","Whether acetylation is direct or via an associated activity not fully excluded","Reproducibility across labs not established"]},{"year":null,"claim":"Whether NAA10 possesses bona fide internal lysine-acetyltransferase activity in vivo, and which physiological substrates it acetylates beyond NatA-type N-termini, remains unresolved.","evidence":"Conflicting reconstitution and cell-based studies","pmids":[],"confidence":"Low","gaps":["No independently replicated, cofactor-defined demonstration of cellular KAT activity","Mechanistic basis for reconciling positive and negative KAT findings absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,3,6,15]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,22]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,26]}],"complexes":["NatA complex"],"partners":["NAA15","HYPK","NAA12","UBE2M","RBX1","CUL4A","C7ORF50","NME3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P41227","full_name":"N-alpha-acetyltransferase 10","aliases":["N-terminal acetyltransferase complex ARD1 subunit homolog A","hARD1","NatA catalytic subunit Naa10"],"length_aa":235,"mass_kda":26.5,"function":"Catalytic subunit of N-terminal acetyltransferase complexes which display alpha (N-terminal) acetyltransferase activity (PubMed:15496142, PubMed:19420222, PubMed:19826488, PubMed:20145209, PubMed:20154145, PubMed:25489052, PubMed:27708256, PubMed:29754825, PubMed:32042062). Acetylates amino termini that are devoid of initiator methionine (PubMed:19420222). The alpha (N-terminal) acetyltransferase activity may be important for vascular, hematopoietic and neuronal growth and development. Without NAA15, displays epsilon (internal) acetyltransferase activity towards HIF1A, thereby promoting its degradation (PubMed:12464182). Represses MYLK kinase activity by acetylation, and thus represses tumor cell migration (PubMed:19826488). Acetylates, and stabilizes TSC2, thereby repressing mTOR activity and suppressing cancer development (PubMed:20145209). Acetylates HSPA1A and HSPA1B at 'Lys-77' which enhances its chaperone activity and leads to preferential binding to co-chaperone HOPX (PubMed:27708256). Acetylates HIST1H4A (PubMed:29754825). Acts as a negative regulator of sister chromatid cohesion during mitosis (PubMed:27422821)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P41227/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NAA10","classification":"Common Essential","n_dependent_lines":1123,"n_total_lines":1208,"dependency_fraction":0.929635761589404},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"INPPL1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NAA10","total_profiled":1310},"omim":[{"mim_id":"619497","title":"N-ALPHA-ACETYLTRANSFERASE 16, NatA AUXILIARY SUBUNIT; NAA16","url":"https://www.omim.org/entry/619497"},{"mim_id":"619432","title":"N-ALPHA-ACETYLTRANSFERASE 11, NatA CATALYTIC SUBUNIT; NAA11","url":"https://www.omim.org/entry/619432"},{"mim_id":"617787","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 50, WITH BEHAVIORAL ABNORMALITIES; MRD50","url":"https://www.omim.org/entry/617787"},{"mim_id":"608000","title":"N-ALPHA-ACETYLTRANSFERASE 15, NatA AUXILIARY SUBUNIT; NAA15","url":"https://www.omim.org/entry/608000"},{"mim_id":"607073","title":"N-ALPHA-ACETYLTRANSFERASE 80, NatH CATALYTIC SUBUNIT; NAA80","url":"https://www.omim.org/entry/607073"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NAA10"},"hgnc":{"alias_symbol":["DXS707","TE2"],"prev_symbol":["ARD1","ARD1A"]},"alphafold":{"accession":"P41227","domains":[{"cath_id":"3.40.630.30","chopping":"1-156","consensus_level":"high","plddt":97.0773,"start":1,"end":156}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P41227","model_url":"https://alphafold.ebi.ac.uk/files/AF-P41227-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P41227-F1-predicted_aligned_error_v6.png","plddt_mean":80.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NAA10","jax_strain_url":"https://www.jax.org/strain/search?query=NAA10"},"sequence":{"accession":"P41227","fasta_url":"https://rest.uniprot.org/uniprotkb/P41227.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P41227/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P41227"}},"corpus_meta":[{"pmid":"24431331","id":"PMC_24431331","title":"A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome.","date":"2014","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24431331","citation_count":88,"is_preprint":false},{"pmid":"25987439","id":"PMC_25987439","title":"The biological functions of Naa10 - 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In a yeast complementation model, wild-type human NatA fully rescued NatA-deletion yeast phenotypes whereas the S37P mutant only partially rescued, and quantitative Nt-acetylome analysis showed globally reduced N-terminal acetylation of NatA substrates in yeast expressing the mutant compared to wild-type hNatA.\",\n      \"method\": \"Yeast complementation (genetic epistasis), immunoprecipitation, in vitro N-terminal acetylation assay, quantitative Nt-acetylome proteomics\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (in vitro assay, Co-IP, quantitative proteomics, genetic complementation) in a single rigorous study\",\n      \"pmids\": [\"24408909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Recombinant Naa10/ARD1 does not acetylate lysine residues of reported substrates (MSRA, MLCK, RUNX2) above background levels in vitro, suggesting previously reported lysine acetylation events are chemical rather than enzymatic; no difference was detected with or without Naa10 in the reaction.\",\n      \"method\": \"In vitro reconstitution acetylation assay with recombinant proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro reconstitution with purified recombinant proteins, explicitly negative result replicated across multiple proposed substrates in a single focused study\",\n      \"pmids\": [\"26755727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NAA10 is the catalytic subunit of the NatA complex (with auxiliary subunit NAA15); in vitro N-terminal acetylation assays showed that disease-associated missense variants (including p.Ser37Pro) have reduced catalytic activity, and phenotypic severity correlates with the degree of residual NatA catalytic activity.\",\n      \"method\": \"In vitro N-terminal acetylation assays\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay replicated across multiple variants, single lab\",\n      \"pmids\": [\"25099252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Zebrafish Naa10 (zNaa10) possesses N-terminal acetyltransferase activity with substrate specificity highly similar to human NAA10, as demonstrated by in vitro NAT assays; morpholino-mediated knockdown of naa10 in zebrafish caused increased lethality, growth retardation, bent axis, abnormal eyes and bent tails, establishing an essential developmental role.\",\n      \"method\": \"In vitro N-terminal acetylation assay; morpholino knockdown in zebrafish with phenotypic readout\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzymatic assay plus in vivo loss-of-function with defined developmental phenotypes, single lab\",\n      \"pmids\": [\"26251455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The NAA10 p.Tyr43Ser mutant shows significantly decreased catalytic activity and reduced protein stability compared to wild-type in in vitro assays, demonstrating that the Tyr43 residue is important for both enzymatic activity and stability.\",\n      \"method\": \"In vitro N-terminal acetylation assay; protein stability assessment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic and stability assay, single lab, single study\",\n      \"pmids\": [\"26522270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In vitro enzymatic assays for NAA10 missense variants p.Arg83Cys and p.Phe128Leu revealed reduced catalytic N-terminal acetyltransferase activity, linking these variants to pathogenicity.\",\n      \"method\": \"In vitro N-terminal acetylation assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay for multiple variants, single lab\",\n      \"pmids\": [\"27094817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biochemical analyses of NAA10 and NAA15 variants as part of the human NatA complex, including with and without the HYPK regulatory subunit, showed variant-specific impairment of N-terminal acetyltransferase activity, with HYPK modulating NatA enzymatic activity.\",\n      \"method\": \"In vitro N-terminal acetylation assay with reconstituted NatA complex ± HYPK\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted complex enzymatic assays with regulatory subunit, single lab, multiple variants\",\n      \"pmids\": [\"31127942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NAA10 p.Ile72Thr variant is protein-destabilized and has decreased monomeric NAT activity, but NatA complex activity (with NAA15) appears normal; binding to NAA15 is most likely intact, suggesting distinct roles for monomeric NAA10 vs. NatA complex activity.\",\n      \"method\": \"In vitro acetylation assay (monomeric and NatA complex); protein stability studies\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — two orthogonal functional assays (enzymatic, stability), single lab\",\n      \"pmids\": [\"29748569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NAA10 p.V111G has reduced monomeric catalytic activity and reduced protein stability, but NatA complex activity is unaltered, as shown by cycloheximide chase and in vitro acetylation assays; this represents isolated monomeric NAA10 dysfunction without NatA impairment.\",\n      \"method\": \"In vitro N-terminal acetylation assay (monomeric vs. NatA complex); cycloheximide chase\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — two orthogonal functional methods, single lab\",\n      \"pmids\": [\"29558889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NAA10 p.R83H has reduced monomeric catalytic acetyltransferase activity, likely due to impaired enzyme-Ac-CoA binding, as modeled by the altered charge density in the Ac-CoA binding region; NatA complex activity was not separately assessed.\",\n      \"method\": \"In vitro N-terminal acetylation assay (monomeric NAA10); structural modeling\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro assay plus computational modeling, single lab\",\n      \"pmids\": [\"31174490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NAA10 p.His16Pro impairs NatA complex formation and NatA catalytic activity, while monomeric NAA10 catalytic activity and cellular protein stability are unaffected, as shown by immunoprecipitation and in vitro acetylation assays; cycloheximide chase confirmed normal stability.\",\n      \"method\": \"Immunoprecipitation (NatA complex formation); in vitro N-terminal acetylation assay; cycloheximide chase\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus enzymatic assay plus stability assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"32698785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NAA10 p.D10G and p.L11R variants both impair complex formation with NAA15 (shown by immunoprecipitation), but have opposing effects on catalytic activity: D10G retains normal NatA activity but reduced monomeric NAT activity, while L11R shows reduced NatA activity but normal monomeric NAT activity.\",\n      \"method\": \"Immunoprecipitation; in vitro N-terminal acetylation assay (monomeric and NatA complex)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus enzymatic assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"33255974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Monomeric recombinant hARD1/NAA10 exhibits lysine acetyltransferase (KAT) activity in vitro, but this activity is lost as the protein forms oligomers over time; size-exclusion analysis showed oligomeric NAA10 lacks KAT activity while the monomeric form retains it, with activity dependent on reactant concentrations and reaction time.\",\n      \"method\": \"In vitro lysine acetylation assay; size-exclusion chromatography\",\n      \"journal\": \"Molecules (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — single lab, in vitro assay only; contradicted by Magin et al. 2016 (PMID 26755727) which found no KAT activity; conflicting data lowers confidence\",\n      \"pmids\": [\"32013195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NAA10 Trp38 hydroxylation by FIH (factor inhibiting HIF-1α) could not be detected in multiple human cell lines, and no interaction between NAA10 and FIH was found, indicating that Trp38 hydroxylation is not a regulatory switch converting NAA10 from NAT to KAT activity in human cells.\",\n      \"method\": \"Mass spectrometry (hydroxylation detection); Co-IP (NAA10-FIH interaction); cell fractionation in multiple human cell lines\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MS, Co-IP) across multiple cell lines, explicitly negative finding, single lab\",\n      \"pmids\": [\"34769235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Naa12, a previously unannotated Naa10 paralog with NAT activity, genetically compensates for Naa10 in mice; Naa10 single-knockout male mice do not show globally apparent amino-terminal acetylation impairment, but Naa10/Naa12 double-knockout mice are embryonic lethal, establishing Naa12 as a functional redundant enzyme.\",\n      \"method\": \"Mouse knockout genetics (single and double knockout); phenotypic analysis; enzymatic activity assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-knockout genetic epistasis with embryonic lethality, enzymatic activity characterization, replicated in multiple alleles in same study\",\n      \"pmids\": [\"34355692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biochemical characterization of novel NAA10 variants (p.A6P, p.R79C, p.Q129P, p.E157K) by in vitro acetylation assays revealed distinct impacts on N-terminal acetyltransferase activity, with some variants specifically impairing monomeric NAA10 activity while others impair NatA complex activity, suggesting multiple distinct pathogenic mechanisms.\",\n      \"method\": \"In vitro N-terminal acetylation assay (monomeric and NatA complex)\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic in vitro enzymatic characterization of multiple variants, single lab\",\n      \"pmids\": [\"35039925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Naa10 deficiency in mouse embryonic stem cells augments FGF/MAPK signaling and attenuates differentiation towards the epiblast lineage (deviating towards primitive endoderm), demonstrating a role for Naa10-mediated N-terminal acetylation in regulating FGF/MAPK pathway activity and epiblast specification.\",\n      \"method\": \"Naa10 knockout mESCs; differentiation assays; pathway analysis\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined cellular phenotype with pathway placement (FGF/MAPK), single lab, single study\",\n      \"pmids\": [\"30993557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"siRNA screen identified NAA10 as a factor in the transcriptional machinery regulating PXR (pregnane X receptor) transcription in pancreatic cancer cells; NAA10 knockdown reduced PXR transcript levels.\",\n      \"method\": \"siRNA library screen; deconvolution validation; qRT-PCR\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA screen with limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"30566892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Stable knockdown of Naa10 in H1299 cells caused morphological changes and, by cDNA microarray, upregulation of netrin-1 (NTN1) and its receptor UNC5B as early downstream targets; this relationship was validated in mouse embryos and upon all-trans retinoic acid treatment, indicating Naa10 negatively regulates NTN1/UNC5B expression.\",\n      \"method\": \"Stable shRNA knockdown; cDNA microarray; validation in mouse embryo tissue; retinoic acid treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, transcriptomic downstream target identification with limited mechanistic follow-up\",\n      \"pmids\": [\"27910960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RGMB-AS1 lncRNA binds to the 82–87 amino acid region of NAA10, stimulating its acetyltransferase activity and promoting the conversion of acetyl-CoA to HMG-CoA, contributing to ferroptosis in NSCLC; this was demonstrated by co-IP and functional assays.\",\n      \"method\": \"Co-immunoprecipitation; in vitro acetyltransferase activity assay; cell and xenograft functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP with functional assay; lncRNA-protein interaction claim with limited mechanistic detail in abstract\",\n      \"pmids\": [\"38574881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NAA10 promotes acetylation of CREBRF, which facilitates BTRC (an E3 ubiquitin ligase)-mediated ubiquitination and degradation of CREBRF, thereby activating endoplasmic reticulum stress and exacerbating renal tubular injury in diabetic kidney disease; interactions confirmed by Co-IP.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination/acetylation assays; knockdown/overexpression in HK-2 cells and STZ mouse model\",\n      \"journal\": \"Journal of diabetes investigation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP with functional rescue; lysine acetylation by NAA10 remains controversial (see PMID 26755727)\",\n      \"pmids\": [\"42262012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"UBE2M promotes neddylation of NAA10 at K148, mediated by the RBX1-CUL4A E3 ligase complex, which enhances NAA10 protein stability and functional activity; knockdown of NAA10 suppressed UBE2M-driven prostate cancer cell proliferation, placing NAA10 downstream of the UBE2M neddylation pathway.\",\n      \"method\": \"Co-immunoprecipitation; mass spectrometry; proximity ligation assay; site-directed mutagenesis (K148); knockdown/overexpression in PCa cells and xenografts\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, MS, PLA (three orthogonal methods), mutagenesis at neddylation site, single lab\",\n      \"pmids\": [\"41857595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NAA10 acetylates C7orf50 at lysine-71/72/76 residues; this acetylation, regulated by mTOR (which phosphorylates NAA10 as a nutritional status-responsive acetyltransferase), determines C7orf50 nucleolar localization and coordinates ribosome biogenesis vs. autophagy in response to nutrient status.\",\n      \"method\": \"In vitro and in vivo acetylation assays; site-directed mutagenesis; localization imaging; mTOR pathway perturbation\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro and in vivo acetylation assays with mutagenesis of target lysines, single lab; KAT activity of NAA10 remains controversial but here supported by mutagenesis\",\n      \"pmids\": [\"42139339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NME3 interacts with NAA10 in human dental pulp stem cells (identified by mass spectrometry and confirmed by colocalization); NAA10 knockdown rescued odontogenic differentiation deficits caused by NME3 silencing, and NAA10 overexpression attenuated NME3 effects, placing NAA10 as a downstream effector of NME3 in regulating RUNX2 nuclear translocation.\",\n      \"method\": \"Mass spectrometry; colocalization imaging; knockdown rescue assay; overexpression assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction by MS and colocalization, functional epistasis by KD rescue, single lab, single study\",\n      \"pmids\": [\"42165278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Computational structural analysis of NAA10 F128I and F128L disease-associated mutations revealed that F128I reduces flexibility of the substrate-binding region (impairing substrate peptide binding), while F128L reduces flexibility of the Ac-CoA binding region, demonstrating two mechanistically distinct paths to catalytic inactivation.\",\n      \"method\": \"Molecular dynamics simulation; structural modeling; conformational plasticity analysis\",\n      \"journal\": \"Computational and structural biotechnology journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no in vitro or in vivo experimental validation reported\",\n      \"pmids\": [\"39610905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Patient fibroblasts from males with the NAA10 c.471+2T→A splice donor mutation lacked full-length NAA10 protein and showed cell proliferation defects; retinol uptake was decreased in patient cells, and expression arrays showed significant dysregulation of genes in the retinoic acid signalling pathway including BMP4, STRA6, and downstream targets of BCOR and canonical WNT.\",\n      \"method\": \"Protein expression (Western blot); cell proliferation assay; retinol uptake assay; expression array\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in patient-derived cells, single lab\",\n      \"pmids\": [\"24431331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Down-regulation of NAA10 in rat OGD/R and MCAO models reversed the attenuation of ERK1/2 phosphorylation normally induced by sevoflurane preconditioning, indicating NAA10 mediates neuroprotective effects through regulation of ERK1/2 phosphorylation.\",\n      \"method\": \"siRNA knockdown in vitro (OGD/R) and in vivo (MCAO); Western blot for phospho-ERK1/2; TTC staining; TUNEL assay\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement via KD with phosphorylation readout, limited mechanistic detail\",\n      \"pmids\": [\"33872734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In a NAA10 knockout (ΔNAA10) glioblastoma cell line generated by CRISPR/Cas9, patient variants p.L126R and p.F128L severely impaired NatA complex formation and altered cellular distribution of NAA10, while p.L126V maintained near-wild-type protein stability and colocalization with NAA15, demonstrating that clinical severity is driven by the specific amino acid substitution's effect on NatA complex assembly.\",\n      \"method\": \"CRISPR/Cas9 NAA10 knockout cell line; GFP-tagged variant re-expression; colocalization imaging with NAA15\",\n      \"journal\": \"Molecular and cellular pediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR null background with variant re-expression and colocalization, orthogonal to prior Co-IP data, single lab\",\n      \"pmids\": [\"41973310\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NAA10 is the catalytic subunit of the NatA N-terminal acetyltransferase complex (with auxiliary subunit NAA15 and regulatory subunit HYPK), responsible for co-translational N-terminal acetylation of ~40–50% of the human proteome; disease-associated missense variants impair either monomeric NAA10 catalytic activity, NatA complex formation/activity, or protein stability—through distinct biochemical mechanisms—and a paralogous enzyme Naa12 can genetically compensate for Naa10 loss in mice; additionally, NAA10 undergoes neddylation (at K148 by the RBX1-CUL4A/UBE2M machinery), participates in regulating FGF/MAPK signaling and retinoic acid pathway gene expression, and has been proposed (though controversially) to also acetylate internal lysine residues of select substrates.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NAA10 is the catalytic subunit of the NatA N-terminal acetyltransferase complex, which it forms with the auxiliary subunit NAA15 to co-translationally acetylate the N-termini of NatA-class substrates [#0, #2]. Its N-terminal acetyltransferase activity and substrate specificity are conserved from zebrafish to human, and loss of function produces essential developmental phenotypes including growth retardation and axis/eye defects [#3]. NAA10 catalytic activity exists in two functionally separable forms — monomeric NAA10 NAT activity and NAA15-dependent NatA complex activity — and disease-associated missense variants impair these through distinct biochemical mechanisms: reduced monomeric catalysis, impaired NatA complex assembly, or decreased protein stability [#7, #8, #10, #11, #15]. The severity of NAA10-related (Ogden) syndrome tracks with the degree to which a given substitution disrupts NatA complex formation and residual catalytic activity [#0, #2, #27]. In mice, the loss of Naa10 is genetically buffered by the paralog Naa12, which retains NAT activity, such that single Naa10 knockout shows no global acetylation defect whereas Naa10/Naa12 double knockout is embryonic lethal [#14]. Beyond its catalytic role, NAA10 is stabilized and activated by neddylation at K148 via the RBX1-CUL4A/UBE2M machinery [#21], and NatA-dependent activity feeds into developmental signaling, modulating FGF/MAPK output and epiblast specification [#16] and retinoic-acid pathway gene expression [#25]. Whether NAA10 acts as a genuine lysine (internal) acetyltransferase is contested: recombinant NAA10 failed to acetylate proposed lysine substrates above background [#1], and Trp38 hydroxylation by FIH proposed to switch NAA10 to a KAT was not detectable in human cells [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established NAA10 as the catalytic subunit of NatA and showed that the Ogden syndrome S37P substitution causes disease by reducing both catalysis and NAA15 complexation, defining a loss-of-function mechanism.\",\n      \"evidence\": \"Yeast complementation, immunoprecipitation, in vitro NAT assay, and quantitative Nt-acetylome proteomics; parallel in vitro NAT assays across variants\",\n      \"pmids\": [\"24408909\", \"25099252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate monomeric NAA10 dysfunction from NatA complex dysfunction\", \"Substrate-level consequences in human cells not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked NAA10 loss to a defined human cellular phenotype, showing protein loss disrupts proliferation and dysregulates retinoic-acid pathway gene expression.\",\n      \"evidence\": \"Patient fibroblasts with splice-donor mutation; Western blot, proliferation, retinol uptake, and expression arrays\",\n      \"pmids\": [\"24431331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct acetylation substrates linking NAA10 to retinoic-acid genes not identified\", \"Causality vs. correlation of transcriptional changes unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated conservation of NAA10 NAT activity and substrate specificity and an essential developmental requirement in a vertebrate model.\",\n      \"evidence\": \"In vitro NAT assay of zebrafish Naa10; morpholino knockdown with developmental phenotyping\",\n      \"pmids\": [\"26251455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino off-target effects not fully excluded\", \"Specific substrates underlying developmental phenotypes unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Challenged the proposed lysine-acetyltransferase function by showing recombinant NAA10 does not acetylate reported KAT substrates above background.\",\n      \"evidence\": \"In vitro reconstitution acetylation assays with purified recombinant proteins across multiple substrates (MSRA, MLCK, RUNX2)\",\n      \"pmids\": [\"26755727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cannot exclude KAT activity requiring cofactors or partners absent in vitro\", \"Does not address context-specific KAT activity in cells\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved that monomeric NAA10 catalysis and NatA complex catalysis are functionally separable, with variants able to impair one while sparing the other.\",\n      \"evidence\": \"In vitro NAT assays of monomeric vs. NatA complex plus cycloheximide chase for p.I72T and p.V111G\",\n      \"pmids\": [\"29748569\", \"29558889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of monomeric NAA10 activity distinct from NatA not defined\", \"In vivo substrates of monomeric form unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed HYPK modulates reconstituted NatA enzymatic activity and that variants impair complex activity in a subunit-context-dependent manner.\",\n      \"evidence\": \"In vitro NAT assays with reconstituted NatA ±HYPK across variants; additional monomeric assays with Ac-CoA-binding structural modeling\",\n      \"pmids\": [\"31127942\", \"31174490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HYPK regulatory mechanism at residue level not resolved\", \"Cellular relevance of HYPK modulation not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed NAA10-mediated acetylation upstream of developmental signaling, showing Naa10 loss augments FGF/MAPK and biases lineage choice.\",\n      \"evidence\": \"Naa10 knockout mESC differentiation and pathway analysis\",\n      \"pmids\": [\"30993557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NAA10 substrate in the FGF/MAPK axis not identified\", \"Single cellular system\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined distinct pathogenic mechanisms at the assembly level, with variants selectively disrupting NatA complex formation, monomeric catalysis, or stability, sometimes in opposing directions.\",\n      \"evidence\": \"Immunoprecipitation and in vitro NAT assays (monomeric and complex) plus cycloheximide chase for p.H16P, p.D10G, p.L11R\",\n      \"pmids\": [\"32698785\", \"33255974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype-phenotype correlation for opposing biochemical effects not clinically resolved\", \"Single-lab biochemistry\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed genetic redundancy by identifying the paralog Naa12, explaining the mild single-knockout phenotype and establishing combined NAT activity as essential for viability.\",\n      \"evidence\": \"Mouse single and double knockout genetics with enzymatic activity assays\",\n      \"pmids\": [\"34355692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative substrate division between Naa10 and Naa12 in vivo not mapped\", \"Tissue-specific dependence unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tested and rejected a proposed NAT-to-KAT regulatory switch, finding no NAA10 Trp38 hydroxylation or FIH interaction in human cells.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, and cell fractionation across multiple human cell lines (negative result)\",\n      \"pmids\": [\"34769235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cannot exclude transient or condition-specific hydroxylation\", \"Does not resolve KAT activity question broadly\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified neddylation at K148 by RBX1-CUL4A/UBE2M as a post-translational input that stabilizes and activates NAA10, integrating it into the neddylation signaling pathway.\",\n      \"evidence\": \"Co-IP, mass spectrometry, proximity ligation, K148 mutagenesis, and knockdown in prostate cancer cells and xenografts\",\n      \"pmids\": [\"41857595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream NAA10 substrates mediating proliferation not identified\", \"Generality beyond cancer context untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reopened the lysine-acetyltransferase model with mutagenesis-supported claims that NAA10 acetylates specific lysines on C7orf50 (nutrient/mTOR-responsive) and CREBRF, despite continued controversy over KAT activity.\",\n      \"evidence\": \"In vitro and in vivo acetylation assays with target-lysine mutagenesis, localization imaging, mTOR perturbation; separate Co-IP and ubiquitination/acetylation assays\",\n      \"pmids\": [\"42139339\", \"42262012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conflicts with prior negative reconstitution data (PMID 26755727)\", \"Whether acetylation is direct or via an associated activity not fully excluded\", \"Reproducibility across labs not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether NAA10 possesses bona fide internal lysine-acetyltransferase activity in vivo, and which physiological substrates it acetylates beyond NatA-type N-termini, remains unresolved.\",\n      \"evidence\": \"Conflicting reconstitution and cell-based studies\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No independently replicated, cofactor-defined demonstration of cellular KAT activity\", \"Mechanistic basis for reconciling positive and negative KAT findings absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 3, 6, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 26]}\n    ],\n    \"complexes\": [\"NatA complex\"],\n    \"partners\": [\"NAA15\", \"HYPK\", \"NAA12\", \"UBE2M\", \"RBX1\", \"CUL4A\", \"C7orf50\", \"NME3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}