{"gene":"NAA15","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2005,"finding":"NAA15 (NATH) forms a stable complex with hARD1 (NAA10), as demonstrated by reciprocal immunoprecipitations followed by MS analysis. The NATH-hARD1 complex exhibits N-terminal acetyltransferase activity. Both proteins interact with ribosomal subunits, indicating a co-translational acetyltransferase function. NATH localizes to the cytoplasm. Both NATH and hARD1 are cleaved during apoptosis, resulting in decreased NAT activity.","method":"Reciprocal co-immunoprecipitation with MS confirmation, in vitro acetyltransferase assay, ribosome co-sedimentation, subcellular fractionation/localization, apoptosis assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP with MS, enzymatic activity assay, ribosome binding, and localization all in one study; foundational characterization paper","pmids":["15496142"],"is_preprint":false},{"year":2006,"finding":"RNAi-mediated knockdown of NATH (NAA15) and/or hARD1 (NAA10) triggers apoptosis in human cell lines, demonstrating that the NATH-hARD1 N-terminal acetyltransferase complex is required for cell survival.","method":"RNAi knockdown with apoptosis readout in human cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype (apoptosis), single lab but clear mechanistic link","pmids":["16518407"],"is_preprint":false},{"year":2018,"finding":"NAA15 is the auxiliary subunit of the NatA complex that binds NAA10 (the catalytic subunit); loss-of-function variants in NAA15 confirmed deleterious by functional assays in yeast, consistent with haploinsufficiency impairing NatA-mediated N-terminal acetylation.","method":"Yeast complementation functional assay, exome/genome sequencing, RNA analysis (NMD confirmation)","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast functional complementation with two LGD variants, supported by RNA NMD analysis; single study but two orthogonal methods","pmids":["29656860"],"is_preprint":false},{"year":2018,"finding":"A NAA15 mutant (Naa15 ΔN K6E) derived from S. pombe, which prevents NatA from associating with ribosomes while retaining in vitro NatA-specific activity, is unable to rescue the temperature-sensitive growth phenotype of S. cerevisiae lacking NatA. This demonstrates that ribosome binding by NAA15 is required for NatA's in vivo co-translational N-terminal acetylation function.","method":"Yeast complementation assay (S. pombe NatA in S. cerevisiae nat1Δ background), growth phenotype assay at restrictive temperature","journal":"BMC research notes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis/complementation with defined mutant and clear phenotypic readout; single lab, single method","pmids":["29929531"],"is_preprint":false},{"year":2019,"finding":"NAA15 is the auxiliary and regulatory subunit of the NatA complex (together with NAA10 catalytic subunit and HYPK regulatory subunit). Biochemical and enzymatic analyses of NatA complexes carrying NAA15 or NAA10 missense variants, with and without HYPK, demonstrate variant-specific effects on NatA complex activity that help explain phenotypic differences among patients.","method":"In vitro enzymatic assay of reconstituted NatA complexes with patient-derived variants, with and without HYPK","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic reconstitution with mutagenesis, but single lab and limited variant-specific mechanistic depth reported in abstract","pmids":["31127942"],"is_preprint":false},{"year":2018,"finding":"Naa15 knockdown in C2C12 myoblasts enhanced myoblast fusion, indicating that Naa15 negatively regulates myogenic cell fusion. Morpholino knockdown of zebrafish naa15a and naa15b caused aberrant myotome segmentation and formation of abnormally long myofibres spanning adjacent somites, demonstrating a role for Naa15 in myotome formation and myogenesis.","method":"siRNA knockdown in C2C12 myoblast fusion assay; morpholino knockdown in zebrafish with myotome morphology readout","journal":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotypes in two model systems (cell culture + in vivo zebrafish)","pmids":["30502388"],"is_preprint":false},{"year":2026,"finding":"In zebrafish, naa15a and naa15b co-localize to the early larval myocardium. Double knockout of naa15 results in smaller, lowly contractile, bradycardic ventricles with fewer and smaller cardiomyocytes incapable of proliferation and moderately disorganized myofibrils. Cardiomyocyte-specific re-expression of naa15a partially rescues contractility and growth deficits, confirming an indispensable myocardial-intrinsic function. Ubiquitous mis-expression of human NAA15 achieved complete rescue. Quantitative proteomics of naa15-deficient adult hearts revealed reduced levels of mitochondrial respiratory complex I subunits, and reduced mitochondrial content and function were directly documented in mutant myocardium.","method":"Zebrafish knockout (DKO and reduced dosage), tissue-specific and ubiquitous rescue experiments, quantitative mass spectrometry proteomics, mitochondrial content/function assays, cardiomyocyte morphology and proliferation assays","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods in a single rigorous study: KO phenotype, cell-type-specific rescue, human NAA15 functional rescue, quantitative proteomics, mitochondrial function assays","pmids":["42146379"],"is_preprint":true},{"year":2025,"finding":"Loss of NAA15 in mouse models leads to a substantial increase in neuronal count and aberrant brain development, resulting in repetitive and anxious behaviors. Disorder-associated NAA15 variants impair axon and synapse formation, establishing a cellular mechanism by which NAA15 deficiency contributes to neurodevelopmental disorders.","method":"Mouse knockout model (neuronal count, behavioral assays), functional analysis of patient variants (axon and synapse formation assays)","journal":"Autism research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with specific neuroanatomical and behavioral phenotypes plus variant-specific cellular assays; single lab, two orthogonal approaches","pmids":["39825710"],"is_preprint":false},{"year":2016,"finding":"miRNA-27b was verified to directly target NAA15 (Naa15) by dual luciferase reporter assay. siRNA knockdown of Naa15 or transfection of miRNA-27b mimic into mouse aortic endothelial cells increased tube formation, indicating that Naa15 suppresses angiogenic tube formation downstream of miRNA-27b.","method":"Dual luciferase reporter assay, siRNA knockdown, tube formation assay on Matrigel","journal":"Atherosclerosis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic follow-up; functional link between Naa15 and tube formation established only by KD phenotype without pathway placement","pmids":["27755984"],"is_preprint":false}],"current_model":"NAA15 (NATH) is the auxiliary subunit of the NatA N-terminal acetyltransferase complex: it forms a stable complex with the catalytic subunit NAA10, anchors NatA to ribosomes for co-translational N-terminal acetylation of nascent polypeptides (ribosome binding is required for in vivo function), is essential for cell survival, and plays indispensable roles in cardiomyocyte contractility and growth (partly through maintenance of mitochondrial function), myotome morphogenesis, and neuronal development, with loss-of-function causing neurodevelopmental and cardiac disorders in humans and model organisms."},"narrative":{"mechanistic_narrative":"NAA15 (NATH) is the auxiliary subunit of the NatA N-terminal acetyltransferase complex, forming a stable complex with the catalytic subunit NAA10 that carries out co-translational N-terminal acetylation of nascent polypeptides [PMID:15496142]. NAA15 anchors NatA to ribosomes, and this ribosome association is functionally indispensable: a NAA15 mutant retaining catalytic activity in vitro but unable to bind ribosomes fails to rescue NatA-dependent growth in vivo [PMID:29929531]. The complex is further regulated by HYPK, and patient-derived missense variants in NAA15 or NAA10 produce variant-specific effects on NatA activity [PMID:31127942]. NatA function is essential for cell survival, as depletion of NAA15 or NAA10 triggers apoptosis [PMID:16518407]. Beyond housekeeping acetylation, NAA15 has tissue-specific roles: it is required for cardiomyocyte proliferation, contractility, and growth, in part through maintenance of mitochondrial respiratory complex I content and function [PMID:42146379], for myotome morphogenesis and proper control of myogenic cell fusion [PMID:30502388], and for normal neuronal number, axon and synapse formation [PMID:39825710]. Loss-of-function variants in NAA15 cause neurodevelopmental and cardiac disorders in humans and model organisms [PMID:29656860, PMID:39825710].","teleology":[{"year":2005,"claim":"Established that NAA15 is not an independent enzyme but the stable partner of the catalytic NAA10 subunit, and that the resulting complex is a ribosome-associated, co-translational N-terminal acetyltransferase.","evidence":"Reciprocal Co-IP with MS, in vitro acetyltransferase assay, ribosome co-sedimentation and subcellular fractionation in human cells","pmids":["15496142"],"confidence":"High","gaps":["Did not define which NAA15 region mediates ribosome binding","Substrate specificity of the complex not mapped"]},{"year":2006,"claim":"Showed the NatA complex is required for viability, linking loss of N-terminal acetyltransferase activity to a defined cellular fate.","evidence":"RNAi knockdown of NATH and/or hARD1 with apoptosis readout in human cell lines","pmids":["16518407"],"confidence":"Medium","gaps":["Did not identify which acetylation substrates mediate survival","Single-lab loss-of-function without rescue"]},{"year":2018,"claim":"Demonstrated that ribosome binding by NAA15, rather than catalytic activity per se, is required for NatA's in vivo function, separating enzymatic competence from biological function.","evidence":"Complementation in S. cerevisiae nat1Δ with a ribosome-binding-deficient S. pombe Naa15 mutant that retains in vitro activity; growth at restrictive temperature","pmids":["29929531"],"confidence":"Medium","gaps":["Single method/lab","Mechanism by which ribosome tethering enables co-translational acetylation not structurally resolved"]},{"year":2018,"claim":"Connected human NAA15 loss-of-function variants to disease by confirming they are deleterious in a functional assay, consistent with haploinsufficiency impairing NatA acetylation.","evidence":"Yeast complementation of patient variants, exome/genome sequencing, RNA/NMD analysis","pmids":["29656860"],"confidence":"Medium","gaps":["Tissue-level mechanism of disease not established here","Substrate hypoacetylation in patients not directly measured"]},{"year":2019,"claim":"Refined the regulatory architecture by adding HYPK to the complex and showing patient variants exert variant-specific effects on NatA activity, providing a biochemical basis for phenotypic heterogeneity.","evidence":"In vitro enzymatic assay of reconstituted NatA complexes carrying NAA15/NAA10 missense variants, with and without HYPK","pmids":["31127942"],"confidence":"Medium","gaps":["Single lab","Limited mechanistic depth on how HYPK modulates specific substrates"]},{"year":2018,"claim":"Identified a tissue-specific role in muscle, showing NAA15 negatively regulates myoblast fusion and is required for ordered myotome segmentation.","evidence":"siRNA knockdown in C2C12 fusion assay and morpholino knockdown of naa15a/naa15b in zebrafish with myotome morphology readout","pmids":["30502388"],"confidence":"Medium","gaps":["Whether the muscle phenotype depends on NatA acetylation activity not tested","Relevant acetylation substrates in muscle unknown"]},{"year":2025,"claim":"Defined a neurodevelopmental cellular mechanism, linking NAA15 loss to increased neuronal number and to impaired axon and synapse formation by disorder variants.","evidence":"Mouse knockout (neuronal count, behavior) plus patient-variant axon/synapse formation assays","pmids":["39825710"],"confidence":"Medium","gaps":["Molecular substrates underlying axon/synapse defects not identified","Single lab"]},{"year":2026,"claim":"Established a myocardial-intrinsic, partly mitochondrial mechanism, showing NAA15 is required for cardiomyocyte proliferation and contractility and supports respiratory complex I content.","evidence":"Zebrafish naa15 double knockout, cardiomyocyte-specific and human-NAA15 rescue, quantitative proteomics and mitochondrial function assays (preprint)","pmids":["42146379"],"confidence":"High","gaps":["Whether complex I subunit loss is a direct acetylation consequence not established","Preprint, not yet peer-reviewed"]},{"year":null,"claim":"The specific N-terminally acetylated substrates that mediate NAA15's distinct cardiac, muscle, and neuronal functions remain unidentified.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No substrate-level mechanism linking NatA acetylation to tissue phenotypes","Structural basis of ribosome anchoring in human NatA not resolved in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6,7]}],"complexes":["NatA N-terminal acetyltransferase complex"],"partners":["NAA10","HYPK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BXJ9","full_name":"N-alpha-acetyltransferase 15, NatA auxiliary subunit","aliases":["Gastric cancer antigen Ga19","N-terminal acetyltransferase","NMDA receptor-regulated protein 1","Protein tubedown-1","Tbdn100"],"length_aa":866,"mass_kda":101.3,"function":"Auxillary subunit of N-terminal acetyltransferase complexes which display alpha (N-terminal) acetyltransferase (NAT) activity (PubMed:15496142, PubMed:20154145, PubMed:29754825, PubMed:32042062). The NAT activity may be important for vascular, hematopoietic and neuronal growth and development (PubMed:15496142). Required to control retinal neovascularization in adult ocular endothelial cells (PubMed:11687548). In complex with XRCC6 and XRCC5 (Ku80), up-regulates transcription from the osteocalcin promoter (PubMed:12145306)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BXJ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NAA15","classification":"Common Essential","n_dependent_lines":1179,"n_total_lines":1208,"dependency_fraction":0.9759933774834437},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NAA15","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":"309800","title":"MICROPHTHALMIA, SYNDROMIC 1; MCOPS1","url":"https://www.omim.org/entry/309800"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NAA15"},"hgnc":{"alias_symbol":["TBDN100","NATH","FLJ13340"],"prev_symbol":["NARG1"]},"alphafold":{"accession":"Q9BXJ9","domains":[{"cath_id":"1.25.40.1040","chopping":"9-189","consensus_level":"medium","plddt":93.1032,"start":9,"end":189},{"cath_id":"-","chopping":"239-288","consensus_level":"medium","plddt":96.1432,"start":239,"end":288},{"cath_id":"1.25.40.1010","chopping":"484-573_645-669","consensus_level":"medium","plddt":95.7696,"start":484,"end":669}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXJ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXJ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXJ9-F1-predicted_aligned_error_v6.png","plddt_mean":89.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NAA15","jax_strain_url":"https://www.jax.org/strain/search?query=NAA15"},"sequence":{"accession":"Q9BXJ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXJ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXJ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXJ9"}},"corpus_meta":[{"pmid":"15496142","id":"PMC_15496142","title":"Identification and characterization of the human ARD1-NATH protein acetyltransferase complex.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15496142","citation_count":175,"is_preprint":false},{"pmid":"16518407","id":"PMC_16518407","title":"Induction of apoptosis in human cells by RNAi-mediated knockdown of hARD1 and NATH, components of the protein N-alpha-acetyltransferase complex.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16518407","citation_count":92,"is_preprint":false},{"pmid":"29656860","id":"PMC_29656860","title":"Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29656860","citation_count":75,"is_preprint":false},{"pmid":"31127942","id":"PMC_31127942","title":"Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15.","date":"2019","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31127942","citation_count":59,"is_preprint":false},{"pmid":"12140756","id":"PMC_12140756","title":"NATH, a novel gene overexpressed in papillary thyroid carcinomas.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12140756","citation_count":46,"is_preprint":false},{"pmid":"28990276","id":"PMC_28990276","title":"Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability.","date":"2017","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28990276","citation_count":44,"is_preprint":false},{"pmid":"37130971","id":"PMC_37130971","title":"Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome.","date":"2023","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/37130971","citation_count":43,"is_preprint":false},{"pmid":"33103328","id":"PMC_33103328","title":"Variants in NAA15 cause pediatric hypertrophic cardiomyopathy.","date":"2020","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33103328","citation_count":22,"is_preprint":false},{"pmid":"27755984","id":"PMC_27755984","title":"miRNA-27b modulates endothelial cell angiogenesis by directly targeting Naa15 in atherogenesis.","date":"2016","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/27755984","citation_count":16,"is_preprint":false},{"pmid":"40246269","id":"PMC_40246269","title":"Field guide to Nath's research work on ATP synthesis and hydrolysis.","date":"2025","source":"Bio Systems","url":"https://pubmed.ncbi.nlm.nih.gov/40246269","citation_count":12,"is_preprint":false},{"pmid":"34084768","id":"PMC_34084768","title":"Phenotypic Robustness of Epidermal Stem Cell Number in C. elegans Is Modulated by the Activity of the Conserved N-acetyltransferase nath-10/NAT10.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34084768","citation_count":10,"is_preprint":false},{"pmid":"29929531","id":"PMC_29929531","title":"Investigating the functionality of a ribosome-binding mutant of NAA15 using Saccharomyces cerevisiae.","date":"2018","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/29929531","citation_count":9,"is_preprint":false},{"pmid":"30502388","id":"PMC_30502388","title":"Naa15 knockdown enhances c2c12 myoblast fusion and induces defects in zebrafish myotome morphogenesis.","date":"2018","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30502388","citation_count":6,"is_preprint":false},{"pmid":"29621621","id":"PMC_29621621","title":"Phenotypic consequences of gene disruption by a balanced de novo translocation involving SLC6A1 and NAA15.","date":"2018","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29621621","citation_count":4,"is_preprint":false},{"pmid":"39825710","id":"PMC_39825710","title":"Naa15 Haploinsufficiency and De Novo Missense Variants Associate With Neurodevelopmental Disorders and Interfere With Neurogenesis and Neuron Development.","date":"2025","source":"Autism research : official journal of the International Society for Autism Research","url":"https://pubmed.ncbi.nlm.nih.gov/39825710","citation_count":3,"is_preprint":false},{"pmid":"42091191","id":"PMC_42091191","title":"[Clinical and genetic analysis of four Chinese pedigrees affected with NAA15-related intellectual developmental disorder].","date":"2026","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/42091191","citation_count":0,"is_preprint":false},{"pmid":"42146379","id":"PMC_42146379","title":"Mitochondrial dysfunction underlies cardiac contractility and growth defects in a zebrafish model of NAA15 -related heart disease.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42146379","citation_count":0,"is_preprint":false},{"pmid":"26368697","id":"PMC_26368697","title":"Nonlinear Raman-Nath diffraction of femtosecond laser pulses in a 2D nonlinear photonic crystal.","date":"2015","source":"Optics letters","url":"https://pubmed.ncbi.nlm.nih.gov/26368697","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.04.668548","title":"Mitochondrial dysfunction underlies cardiac contractility and growth defects in a zebrafish model of  <i>NAA15</i>  -related heart disease","date":"2025-08-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.04.668548","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11730,"output_tokens":2450,"usd":0.03597,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9602,"output_tokens":2695,"usd":0.057693,"stage2_stop_reason":"end_turn"},"total_usd":0.093663,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"NAA15 (NATH) forms a stable complex with hARD1 (NAA10), as demonstrated by reciprocal immunoprecipitations followed by MS analysis. The NATH-hARD1 complex exhibits N-terminal acetyltransferase activity. Both proteins interact with ribosomal subunits, indicating a co-translational acetyltransferase function. NATH localizes to the cytoplasm. Both NATH and hARD1 are cleaved during apoptosis, resulting in decreased NAT activity.\",\n      \"method\": \"Reciprocal co-immunoprecipitation with MS confirmation, in vitro acetyltransferase assay, ribosome co-sedimentation, subcellular fractionation/localization, apoptosis assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP with MS, enzymatic activity assay, ribosome binding, and localization all in one study; foundational characterization paper\",\n      \"pmids\": [\"15496142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RNAi-mediated knockdown of NATH (NAA15) and/or hARD1 (NAA10) triggers apoptosis in human cell lines, demonstrating that the NATH-hARD1 N-terminal acetyltransferase complex is required for cell survival.\",\n      \"method\": \"RNAi knockdown with apoptosis readout in human cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype (apoptosis), single lab but clear mechanistic link\",\n      \"pmids\": [\"16518407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NAA15 is the auxiliary subunit of the NatA complex that binds NAA10 (the catalytic subunit); loss-of-function variants in NAA15 confirmed deleterious by functional assays in yeast, consistent with haploinsufficiency impairing NatA-mediated N-terminal acetylation.\",\n      \"method\": \"Yeast complementation functional assay, exome/genome sequencing, RNA analysis (NMD confirmation)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast functional complementation with two LGD variants, supported by RNA NMD analysis; single study but two orthogonal methods\",\n      \"pmids\": [\"29656860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A NAA15 mutant (Naa15 ΔN K6E) derived from S. pombe, which prevents NatA from associating with ribosomes while retaining in vitro NatA-specific activity, is unable to rescue the temperature-sensitive growth phenotype of S. cerevisiae lacking NatA. This demonstrates that ribosome binding by NAA15 is required for NatA's in vivo co-translational N-terminal acetylation function.\",\n      \"method\": \"Yeast complementation assay (S. pombe NatA in S. cerevisiae nat1Δ background), growth phenotype assay at restrictive temperature\",\n      \"journal\": \"BMC research notes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis/complementation with defined mutant and clear phenotypic readout; single lab, single method\",\n      \"pmids\": [\"29929531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NAA15 is the auxiliary and regulatory subunit of the NatA complex (together with NAA10 catalytic subunit and HYPK regulatory subunit). Biochemical and enzymatic analyses of NatA complexes carrying NAA15 or NAA10 missense variants, with and without HYPK, demonstrate variant-specific effects on NatA complex activity that help explain phenotypic differences among patients.\",\n      \"method\": \"In vitro enzymatic assay of reconstituted NatA complexes with patient-derived variants, with and without HYPK\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic reconstitution with mutagenesis, but single lab and limited variant-specific mechanistic depth reported in abstract\",\n      \"pmids\": [\"31127942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Naa15 knockdown in C2C12 myoblasts enhanced myoblast fusion, indicating that Naa15 negatively regulates myogenic cell fusion. Morpholino knockdown of zebrafish naa15a and naa15b caused aberrant myotome segmentation and formation of abnormally long myofibres spanning adjacent somites, demonstrating a role for Naa15 in myotome formation and myogenesis.\",\n      \"method\": \"siRNA knockdown in C2C12 myoblast fusion assay; morpholino knockdown in zebrafish with myotome morphology readout\",\n      \"journal\": \"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotypes in two model systems (cell culture + in vivo zebrafish)\",\n      \"pmids\": [\"30502388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In zebrafish, naa15a and naa15b co-localize to the early larval myocardium. Double knockout of naa15 results in smaller, lowly contractile, bradycardic ventricles with fewer and smaller cardiomyocytes incapable of proliferation and moderately disorganized myofibrils. Cardiomyocyte-specific re-expression of naa15a partially rescues contractility and growth deficits, confirming an indispensable myocardial-intrinsic function. Ubiquitous mis-expression of human NAA15 achieved complete rescue. Quantitative proteomics of naa15-deficient adult hearts revealed reduced levels of mitochondrial respiratory complex I subunits, and reduced mitochondrial content and function were directly documented in mutant myocardium.\",\n      \"method\": \"Zebrafish knockout (DKO and reduced dosage), tissue-specific and ubiquitous rescue experiments, quantitative mass spectrometry proteomics, mitochondrial content/function assays, cardiomyocyte morphology and proliferation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods in a single rigorous study: KO phenotype, cell-type-specific rescue, human NAA15 functional rescue, quantitative proteomics, mitochondrial function assays\",\n      \"pmids\": [\"42146379\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of NAA15 in mouse models leads to a substantial increase in neuronal count and aberrant brain development, resulting in repetitive and anxious behaviors. Disorder-associated NAA15 variants impair axon and synapse formation, establishing a cellular mechanism by which NAA15 deficiency contributes to neurodevelopmental disorders.\",\n      \"method\": \"Mouse knockout model (neuronal count, behavioral assays), functional analysis of patient variants (axon and synapse formation assays)\",\n      \"journal\": \"Autism research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with specific neuroanatomical and behavioral phenotypes plus variant-specific cellular assays; single lab, two orthogonal approaches\",\n      \"pmids\": [\"39825710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miRNA-27b was verified to directly target NAA15 (Naa15) by dual luciferase reporter assay. siRNA knockdown of Naa15 or transfection of miRNA-27b mimic into mouse aortic endothelial cells increased tube formation, indicating that Naa15 suppresses angiogenic tube formation downstream of miRNA-27b.\",\n      \"method\": \"Dual luciferase reporter assay, siRNA knockdown, tube formation assay on Matrigel\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic follow-up; functional link between Naa15 and tube formation established only by KD phenotype without pathway placement\",\n      \"pmids\": [\"27755984\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NAA15 (NATH) is the auxiliary subunit of the NatA N-terminal acetyltransferase complex: it forms a stable complex with the catalytic subunit NAA10, anchors NatA to ribosomes for co-translational N-terminal acetylation of nascent polypeptides (ribosome binding is required for in vivo function), is essential for cell survival, and plays indispensable roles in cardiomyocyte contractility and growth (partly through maintenance of mitochondrial function), myotome morphogenesis, and neuronal development, with loss-of-function causing neurodevelopmental and cardiac disorders in humans and model organisms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NAA15 (NATH) is the auxiliary subunit of the NatA N-terminal acetyltransferase complex, forming a stable complex with the catalytic subunit NAA10 that carries out co-translational N-terminal acetylation of nascent polypeptides [#0]. NAA15 anchors NatA to ribosomes, and this ribosome association is functionally indispensable: a NAA15 mutant retaining catalytic activity in vitro but unable to bind ribosomes fails to rescue NatA-dependent growth in vivo [#3]. The complex is further regulated by HYPK, and patient-derived missense variants in NAA15 or NAA10 produce variant-specific effects on NatA activity [#4]. NatA function is essential for cell survival, as depletion of NAA15 or NAA10 triggers apoptosis [#1]. Beyond housekeeping acetylation, NAA15 has tissue-specific roles: it is required for cardiomyocyte proliferation, contractility, and growth, in part through maintenance of mitochondrial respiratory complex I content and function [#6], for myotome morphogenesis and proper control of myogenic cell fusion [#5], and for normal neuronal number, axon and synapse formation [#7]. Loss-of-function variants in NAA15 cause neurodevelopmental and cardiac disorders in humans and model organisms [#2, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that NAA15 is not an independent enzyme but the stable partner of the catalytic NAA10 subunit, and that the resulting complex is a ribosome-associated, co-translational N-terminal acetyltransferase.\",\n      \"evidence\": \"Reciprocal Co-IP with MS, in vitro acetyltransferase assay, ribosome co-sedimentation and subcellular fractionation in human cells\",\n      \"pmids\": [\"15496142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which NAA15 region mediates ribosome binding\", \"Substrate specificity of the complex not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed the NatA complex is required for viability, linking loss of N-terminal acetyltransferase activity to a defined cellular fate.\",\n      \"evidence\": \"RNAi knockdown of NATH and/or hARD1 with apoptosis readout in human cell lines\",\n      \"pmids\": [\"16518407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify which acetylation substrates mediate survival\", \"Single-lab loss-of-function without rescue\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that ribosome binding by NAA15, rather than catalytic activity per se, is required for NatA's in vivo function, separating enzymatic competence from biological function.\",\n      \"evidence\": \"Complementation in S. cerevisiae nat1\\u0394 with a ribosome-binding-deficient S. pombe Naa15 mutant that retains in vitro activity; growth at restrictive temperature\",\n      \"pmids\": [\"29929531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method/lab\", \"Mechanism by which ribosome tethering enables co-translational acetylation not structurally resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected human NAA15 loss-of-function variants to disease by confirming they are deleterious in a functional assay, consistent with haploinsufficiency impairing NatA acetylation.\",\n      \"evidence\": \"Yeast complementation of patient variants, exome/genome sequencing, RNA/NMD analysis\",\n      \"pmids\": [\"29656860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-level mechanism of disease not established here\", \"Substrate hypoacetylation in patients not directly measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined the regulatory architecture by adding HYPK to the complex and showing patient variants exert variant-specific effects on NatA activity, providing a biochemical basis for phenotypic heterogeneity.\",\n      \"evidence\": \"In vitro enzymatic assay of reconstituted NatA complexes carrying NAA15/NAA10 missense variants, with and without HYPK\",\n      \"pmids\": [\"31127942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Limited mechanistic depth on how HYPK modulates specific substrates\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a tissue-specific role in muscle, showing NAA15 negatively regulates myoblast fusion and is required for ordered myotome segmentation.\",\n      \"evidence\": \"siRNA knockdown in C2C12 fusion assay and morpholino knockdown of naa15a/naa15b in zebrafish with myotome morphology readout\",\n      \"pmids\": [\"30502388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the muscle phenotype depends on NatA acetylation activity not tested\", \"Relevant acetylation substrates in muscle unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a neurodevelopmental cellular mechanism, linking NAA15 loss to increased neuronal number and to impaired axon and synapse formation by disorder variants.\",\n      \"evidence\": \"Mouse knockout (neuronal count, behavior) plus patient-variant axon/synapse formation assays\",\n      \"pmids\": [\"39825710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrates underlying axon/synapse defects not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a myocardial-intrinsic, partly mitochondrial mechanism, showing NAA15 is required for cardiomyocyte proliferation and contractility and supports respiratory complex I content.\",\n      \"evidence\": \"Zebrafish naa15 double knockout, cardiomyocyte-specific and human-NAA15 rescue, quantitative proteomics and mitochondrial function assays (preprint)\",\n      \"pmids\": [\"42146379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether complex I subunit loss is a direct acetylation consequence not established\", \"Preprint, not yet peer-reviewed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific N-terminally acetylated substrates that mediate NAA15's distinct cardiac, muscle, and neuronal functions remain unidentified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate-level mechanism linking NatA acetylation to tissue phenotypes\", \"Structural basis of ribosome anchoring in human NatA not resolved in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"complexes\": [\"NatA N-terminal acetyltransferase complex\"],\n    \"partners\": [\"NAA10\", \"HYPK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}