Affinage

NAA15

N-alpha-acetyltransferase 15, NatA auxiliary subunit · UniProt Q9BXJ9

Length
866 aa
Mass
101.3 kDa
Annotated
2026-04-29
17 papers in source corpus 8 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NAA15 is the auxiliary scaffolding subunit of the NatA N-terminal acetyltransferase complex, essential for co-translational N-terminal acetylation of a large fraction of the proteome. NAA15 forms a stable complex with the catalytic subunit NAA10 and the regulatory subunit HYPK, is required for proper folding and enzymatic activity of NAA10, and anchors the complex to the ribosome to enable co-translational acetylation; a ribosome-binding-deficient mutant retains catalytic activity in vitro but fails to support growth in vivo (PMID:15496142, PMID:29929531, PMID:31127942). Loss of NAA15 triggers apoptosis in human cells, disrupts cardiomyocyte proliferation and mitochondrial complex I protein levels in zebrafish hearts, causes myotome segmentation defects in zebrafish, and impairs neuronal axon and synapse formation in mice, leading to neurodevelopmental phenotypes including increased neuronal count and behavioral abnormalities (PMID:16518407, PMID:30502388, PMID:39825710). Haploinsufficiency of NAA15 through loss-of-function variants reduces NatA acetyltransferase activity and causes neurodevelopmental and congenital heart disorders (PMID:29656860).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2005 High

    The identity and biochemical function of the human NatA complex were established: NAA15 (NATH) forms a stable complex with NAA10 (hARD1) that possesses N-terminal acetyltransferase activity and associates with ribosomes, placing NatA as a co-translational acetylation machine.

    Evidence Reciprocal co-immunoprecipitation/MS, in vitro acetyltransferase assay, ribosome co-sedimentation, and subcellular fractionation in human cells

    PMID:15496142

    Open questions at the time
    • Structural basis of NAA15–NAA10 interaction not resolved
    • Precise ribosome-binding interface of NAA15 unknown
    • Full substrate repertoire of NatA not defined
  2. 2006 Medium

    The NatA complex was shown to be essential for cell viability: both subunits are cleaved during apoptosis and their knockdown independently triggers apoptosis, establishing a pro-survival requirement for NatA-mediated acetylation.

    Evidence siRNA knockdown of NAA15/NAA10 with apoptosis readouts; Western blotting of apoptotic cells

    PMID:15496142 PMID:16518407

    Open questions at the time
    • Identity of critical NatA substrates whose loss of acetylation triggers apoptosis unknown
    • Pathway connecting NatA loss to caspase activation not delineated
  3. 2018 Medium

    The scaffolding role of NAA15 was dissected mechanistically: NAA15 is required for NAA10 folding and ribosome anchoring, and a ribosome-binding-deficient NAA15 mutant retains catalytic activity in vitro yet cannot support yeast growth, proving the in vivo essentiality of co-translational NatA function.

    Evidence Yeast complementation assay with S. pombe NatA ribosome-binding mutant (ΔN K6E) in S. cerevisiae naa15Δ; in vitro acetyltransferase assay

    PMID:29929531

    Open questions at the time
    • Structural details of ribosome–NAA15 interface not mapped at residue level
    • Post-translational NatA activity contribution remains unquantified in metazoans
  4. 2018 Medium

    Haploinsufficiency was established as the disease mechanism for NAA15 loss-of-function variants: nonsense and gene-disrupting variants trigger nonsense-mediated decay and reduce NatA activity in yeast complementation assays, linking NAA15 to neurodevelopmental and congenital heart disorders.

    Evidence RNA analysis confirming NMD, yeast functional complementation assay for patient-derived variants

    PMID:29656860

    Open questions at the time
    • Specific downstream substrates mediating disease phenotypes not identified
    • Genotype–phenotype correlations across different variant classes incomplete
  5. 2019 High

    The tripartite NatA complex (NAA15–NAA10–HYPK) was reconstituted, showing that NAA15 modulates both enzymatic activity and substrate specificity of NAA10, and that HYPK further tunes this regulation.

    Evidence Reconstituted NatA complex enzymatic assay with and without HYPK; biochemical analysis of missense variants

    PMID:31127942

    Open questions at the time
    • How HYPK and NAA15 coordinately select substrates at the structural level not resolved
    • Impact of disease-associated missense variants on HYPK interaction not fully characterized
  6. 2018 Medium

    NAA15 was shown to regulate myogenic cell fusion and myotome morphogenesis: knockdown enhances myoblast fusion in C2C12 cells, and zebrafish Naa15a/b morphants exhibit U-shaped myotome defects and elongated myofibres.

    Evidence siRNA screen in C2C12 cells (fusion assay); morpholino knockdown in zebrafish with myotome morphology readout

    PMID:30502388

    Open questions at the time
    • Acetylation substrates mediating myotome boundary formation not identified
    • Whether NAA15's myogenic role is cell-autonomous not resolved
  7. 2025 Medium

    NAA15's role in cardiac development was defined at the cellular and proteomic level: zebrafish naa15 null mutants have hypoplastic, bradycardic hearts with reduced cardiomyocyte proliferation and downregulated mitochondrial complex I proteins and N-terminal acetylation, rescued by wild-type NAA15 re-expression.

    Evidence Zebrafish knockout with transgenic rescue, quantitative N-terminal acetylome proteomics, mitochondrial imaging (preprint)

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Whether complex I protein downregulation is a direct acetylation-dependent effect or secondary not established
    • Mammalian cardiac model confirmation lacking
  8. 2025 Medium

    NAA15 deficiency was linked to aberrant neuronal development and behavior: mouse NAA15 loss-of-function increases neuronal count and causes anxious/repetitive behaviors, while disease-associated variants impair axon and synapse formation in cultured neurons.

    Evidence Mouse knockout model with neuronal counting and behavioral assays; neuronal cultures expressing NDD-associated variants with morphological readouts

    PMID:39825710

    Open questions at the time
    • Specific acetylation substrates driving neuronal phenotypes not identified
    • Whether increased neuronal count reflects impaired apoptosis or excess proliferation not resolved
    • Single study; independent replication in another mammalian system pending

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of critical NatA acetylation substrates whose loss of modification drives specific disease phenotypes (cardiac, neuronal, myogenic) remains unknown, as does the structural basis of NAA15-mediated substrate specificity modulation at the ribosome.
  • No substrate-specific rescue experiments linking individual acetylation events to phenotypic outcomes
  • High-resolution structure of NatA on the ribosome in a mammalian system not available
  • Relative contributions of co-translational versus post-translational NatA activity in metazoans unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0016740 transferase activity 3
Localization
GO:0005840 ribosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 2
Partners
HYPKNAA10
Complex memberships
NatA

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Human NAA15 (NATH) forms a stable complex with hARD1 (NAA10), as demonstrated by reciprocal co-immunoprecipitations followed by MS analysis. The NATH-hARD1 complex exhibits N-terminal acetyltransferase activity, and both subunits interact with ribosomal subunits, indicating a co-translational acetyltransferase function. NAA15 localizes to the cytoplasm, while hARD1 localizes to both cytoplasm and nucleus. Reciprocal co-immunoprecipitation with MS analysis, in vitro acetyltransferase activity assay, ribosome co-sedimentation, subcellular fractionation/immunofluorescence The Biochemical journal High 15496142
2005 NATH (NAA15) and hARD1 (NAA10) are cleaved during apoptosis, resulting in decreased N-terminal acetyltransferase activity, linking the NatA complex to cell survival. Western blotting of apoptotic cells, in vitro acetyltransferase activity assay The Biochemical journal Medium 15496142
2006 RNAi-mediated knockdown of NAA15 (NATH) and/or NAA10 (hARD1) triggers apoptosis in human cell lines, demonstrating that the NatA N-terminal acetyltransferase complex is essential for cell survival. siRNA knockdown with apoptosis readout (cell viability, caspase activation) in human cell lines Oncogene Medium 16518407
2018 NAA15 is the auxiliary subunit of the NatA complex required for proper folding of the catalytic subunit NAA10 and for anchoring the complex to the ribosome. A NAA15 ribosome-binding mutant (ΔN K6E) retains NatA-specific activity in vitro but cannot rescue the temperature-sensitive growth phenotype of budding yeast lacking NatA, demonstrating the essential in vivo importance of co-translational (ribosome-associated) N-terminal acetylation by NatA. Yeast complementation assay (S. pombe NatA mutant expressed in S. cerevisiae naa15Δ), in vitro acetyltransferase assay BMC research notes Medium 29929531
2018 Loss-of-function (likely gene-disrupting) variants in NAA15, including those causing nonsense-mediated decay, reduce NatA-mediated N-terminal acetyltransferase activity. Functional assays in yeast confirmed a deleterious effect of two LGD variants in NAA15 on NatA function, establishing haploinsufficiency as the disease mechanism. RNA analysis (NMD confirmation), yeast functional complementation assay for LGD variants American journal of human genetics Medium 29656860
2019 NAA15 acts as the auxiliary and regulatory scaffold subunit of the NatA complex together with NAA10 (catalytic) and HYPK (regulatory). Biochemical analyses of NatA complex variants with and without the HYPK regulatory subunit demonstrate that NAA15 modulates both the enzymatic activity and substrate specificity of NAA10. Reconstituted NatA complex enzymatic assay with and without HYPK; biochemical analysis of missense variants Human molecular genetics High 31127942
2016 miRNA-27b directly targets NAA15 (Naa15) in mouse aortic endothelial cells, as verified by dual luciferase reporter assay. Knockdown of Naa15 by siRNA or miRNA-27b mimic increases endothelial tube formation, placing NAA15 as a downstream target of miRNA-27b in the regulation of angiogenesis. Dual luciferase reporter assay, siRNA knockdown, tube formation assay on Matrigel Atherosclerosis Medium 27755984
2018 Knockdown of Naa15 in C2C12 myoblasts enhances myoblast fusion, and morpholino-mediated knockdown of zebrafish Naa15a/Naa15b causes U-shaped myotome segmentation defects and abnormally long myofibres, establishing a role for NAA15 in negatively regulating myogenic cell fusion and myotome boundary formation. siRNA screen in C2C12 cells (fusion assay), morpholino knockdown in zebrafish with myotome morphology readout Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology Medium 30502388
2025 In zebrafish, null mutations in naa15a and naa15b cause diminutive, hypocontractile, bradycardic ventricles with fewer and smaller cardiomyocytes incapable of proliferation. Myocardial re-expression of wild-type naa15a or ubiquitous expression of wild-type human NAA15 partially or fully rescues the contractile deficit. Quantitative proteomics of adult naa15 reduced-dosage hearts shows downregulation of mitochondrial respiratory complex I proteins and N-terminally acetylated peptides, and naa15-deficient cardiomyocytes exhibit disrupted mitochondrial density, size, and content, linking NAA15-mediated N-terminal acetylation to mitochondrial function in the heart. Zebrafish knockout model, transgenic rescue, quantitative proteomics (acetylated N-terminal peptide profiling), confocal microscopy of mitochondria, cardiomyocyte proliferation assay bioRxivpreprint Medium
2025 Loss of NAA15 in mice leads to increased neuronal count and aberrant brain development, with associated repetitive and anxious behaviors. Disorder-associated variants in NAA15 impair axon and synapse formation in neurons, establishing a cellular mechanism by which NAA15 deficiency contributes to neurodevelopmental disorders. Mouse loss-of-function model (neuronal count, behavioral assays), neuronal cultures expressing NDD-associated variants (axon/synapse morphology assay) Autism research : official journal of the International Society for Autism Research Medium 39825710

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Identification and characterization of the human ARD1-NATH protein acetyltransferase complex. The Biochemical journal 175 15496142
2006 Induction of apoptosis in human cells by RNAi-mediated knockdown of hARD1 and NATH, components of the protein N-alpha-acetyltransferase complex. Oncogene 92 16518407
2018 Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies. American journal of human genetics 72 29656860
2019 Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15. Human molecular genetics 57 31127942
2002 NATH, a novel gene overexpressed in papillary thyroid carcinomas. Oncogene 46 12140756
2017 Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 43 28990276
2023 Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome. European journal of human genetics : EJHG 42 37130971
2020 Variants in NAA15 cause pediatric hypertrophic cardiomyopathy. American journal of medical genetics. Part A 21 33103328
2016 miRNA-27b modulates endothelial cell angiogenesis by directly targeting Naa15 in atherogenesis. Atherosclerosis 16 27755984
2025 Field guide to Nath's research work on ATP synthesis and hydrolysis. Bio Systems 11 40246269
2021 Phenotypic Robustness of Epidermal Stem Cell Number in C. elegans Is Modulated by the Activity of the Conserved N-acetyltransferase nath-10/NAT10. Frontiers in cell and developmental biology 10 34084768
2018 Investigating the functionality of a ribosome-binding mutant of NAA15 using Saccharomyces cerevisiae. BMC research notes 9 29929531
2022 UBA domain protein SUF1 interacts with NatA-complex subunit NAA15 to regulate thermotolerance in Arabidopsis. Journal of integrative plant biology 8 35524486
2018 Phenotypic consequences of gene disruption by a balanced de novo translocation involving SLC6A1 and NAA15. European journal of medical genetics 4 29621621
2018 Naa15 knockdown enhances c2c12 myoblast fusion and induces defects in zebrafish myotome morphogenesis. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 4 30502388
2025 Naa15 Haploinsufficiency and De Novo Missense Variants Associate With Neurodevelopmental Disorders and Interfere With Neurogenesis and Neuron Development. Autism research : official journal of the International Society for Autism Research 1 39825710
2015 Nonlinear Raman-Nath diffraction of femtosecond laser pulses in a 2D nonlinear photonic crystal. Optics letters 0 26368697