NAA15

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).

1. 2005 High

   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

   PMID:15496142

   Open questions at the time

   • Did not define which NAA15 region mediates ribosome binding
   • Substrate specificity of the complex not mapped
2. 2006 Medium

   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

   PMID:16518407

   Open questions at the time

   • Did not identify which acetylation substrates mediate survival
   • Single-lab loss-of-function without rescue
3. 2018 Medium

   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

   PMID:29929531

   Open questions at the time

   • Single method/lab
   • Mechanism by which ribosome tethering enables co-translational acetylation not structurally resolved
4. 2018 Medium

   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

   PMID:29656860

   Open questions at the time

   • Tissue-level mechanism of disease not established here
   • Substrate hypoacetylation in patients not directly measured
5. 2019 Medium

   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

   PMID:31127942

   Open questions at the time

   • Single lab
   • Limited mechanistic depth on how HYPK modulates specific substrates
6. 2018 Medium

   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

   PMID:30502388

   Open questions at the time

   • Whether the muscle phenotype depends on NatA acetylation activity not tested
   • Relevant acetylation substrates in muscle unknown
7. 2025 Medium

   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

   PMID:39825710

   Open questions at the time

   • Molecular substrates underlying axon/synapse defects not identified
   • Single lab
8. 2026 High

   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)

   PMID:42146379

   Open questions at the time

   • Whether complex I subunit loss is a direct acetylation consequence not established
   • Preprint, not yet peer-reviewed

• The specific N-terminally acetylated substrates that mediate NAA15's distinct cardiac, muscle, and neuronal functions remain unidentified.
• No substrate-level mechanism linking NatA acetylation to tissue phenotypes
• Structural basis of ribosome anchoring in human NatA not resolved in the corpus