id: Q86UY6
gene_symbol: NAA40
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NAA40 (N-alpha-acetyltransferase 40; also NatD/Nat4/Nat11) is a highly substrate-specific N-terminal acetyltransferase that acetylates the free alpha-amino group of the N-terminal serine of histones H4 and H2A (which share an identical Ser-Gly-Arg-Gly N-terminal sequence after initiator-methionine removal), producing N-terminally acetylated H4/H2A (EC 2.3.1.257). Unlike the ribosome-associated NatA/NatB/NatC/NatE complexes, NAA40 is a monomeric enzyme with a narrow, sequence-specific selectivity restricted to these histone N-termini and recognizes the substrate independently of the bulk Nt-acetylation machinery. NAA40-mediated N-terminal acetylation of H4 influences chromatin function and crosstalk with adjacent histone marks (e.g. H4R3 methylation), and NAA40 has reported roles in transcriptional regulation, ribosomal RNA expression, cellular metabolism (including hepatic lipid metabolism), and as a negative regulator of apoptosis. NAA40 localizes mainly to the nucleus with a cytoplasmic pool.
alternative_products:
- name: '1'
  id: Q86UY6-1
- name: '2'
  id: Q86UY6-3
  sequence_note: VSP_054274
- name: '3'
  id: Q86UY6-4
  sequence_note: VSP_054273
existing_annotations:
- term:
    id: GO:0010485
    label: histone H4 acetyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of histone H4 acetyltransferase activity, the core, experimentally established function of NAA40 (N-terminal acetylation of histone H4).
    action: ACCEPT
    reason: NAA40 specifically N-terminally acetylates histone H4; directly demonstrated and conserved across the NatD family.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:0043998
    label: histone H2A acetyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of histone H2A acetyltransferase activity; NAA40 N-terminally acetylates H2A, which shares the H4 N-terminal sequence.
    action: ACCEPT
    reason: Core, experimentally established histone N-terminal acetylation activity of NAA40.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:1990189
    label: protein N-terminal-serine acetyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: NAA40 acetylates the N-terminal serine of histones H4/H2A; this generic N-terminal serine acetyltransferase MF correctly describes the chemistry, but the histone-specific terms capture the biology more precisely.
    action: ACCEPT
    reason: NAA40 is an N-terminal serine acetyltransferase (the H4/H2A N-terminus is Ser); the term is correct and complements the histone-specific MFs.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: specifically recognizes the 'Ser-Gly-Arg-Gly sequence'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: NAA40 acts in the nucleus on chromatin-associated histones H4/H2A.
    action: ACCEPT
    reason: The nucleus is the site of action for NAA40 histone N-terminal acetylation; well supported.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component EXP PMID:25732826
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of nuclear localization, consistent with NAA40's chromatin substrate.
    action: ACCEPT
    reason: Correct localization for histone N-terminal acetylation.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component EXP PMID:25732826
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of a cytoplasmic pool of NAA40.
    action: KEEP_AS_NON_CORE
    reason: A cytoplasmic pool is documented experimentally but NAA40's core histone-acetylation function is nuclear; kept non-core.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component EXP PMID:25732826
- term:
    id: GO:0006338
    label: chromatin remodeling
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Inferred from the histone H4 acetyltransferase MF; N-terminal acetylation of H4 modulates chromatin. The broad "chromatin remodeling" term is a loose fit for a covalent histone-mark-writing activity.
    action: KEEP_AS_NON_CORE
    reason: NAA40 writes a histone N-terminal acetyl mark that affects chromatin function/crosstalk, but it is not a canonical ATP-dependent chromatin remodeler; kept as a non-core process annotation.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0006338 chromatin remodeling biological_process IEA GO_REF:0000108
- term:
    id: GO:0010485
    label: histone H4 acetyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro domain-based electronic annotation of histone H4 acetyltransferase activity, consistent with experimental evidence.
    action: ACCEPT
    reason: Core activity; redundant with IDA/IBA H4 annotations.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:0016747
    label: acyltransferase activity, transferring groups other than amino-acyl groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Generic acyltransferase MF from InterPro; correct but far less informative than the histone N-terminal acetyltransferase terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-level acyltransferase term superseded by the specific histone Nt-acetyltransferase activities.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups molecular_function IEA
- term:
    id: GO:0043998
    label: histone H2A acetyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro domain-based electronic annotation of histone H2A acetyltransferase activity, consistent with experiment.
    action: ACCEPT
    reason: Core activity; redundant with IDA/IBA H2A annotations.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:1990189
    label: protein N-terminal-serine acetyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: RHEA-derived electronic annotation of N-terminal serine acetyltransferase activity (EC 2.3.1.257), reflecting the histone H4/H2A N-terminal Ser substrate.
    action: ACCEPT
    reason: Correct chemistry for NAA40; complements the histone-specific terms.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: specifically recognizes the 'Ser-Gly-Arg-Gly sequence'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: IntAct interaction (histone H2B variant P20290-2) from a high-throughput study. Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; uninformative as a core MF (histone substrate binding is implicit in the catalytic MF).
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:32296183 UniProtKB:P20290-2
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence nucleoplasmic localization, consistent with NAA40's chromatin-associated histone substrate.
    action: ACCEPT
    reason: Correct, specific nuclear localization for histone N-terminal acetylation.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005654 nucleoplasm cellular_component IDA GO_REF:0000052 HPA
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence cytosolic pool of NAA40.
    action: KEEP_AS_NON_CORE
    reason: A cytosolic pool is documented but the core function is nuclear; kept non-core.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component IDA GO_REF:0000052 HPA
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:25732826
  qualifier: located_in
  review:
    summary: Experimental nuclear localization of NAA40.
    action: ACCEPT
    reason: Core localization for histone N-terminal acetylation.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component EXP PMID:25732826
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:25732826
  qualifier: located_in
  review:
    summary: Experimental cytoplasmic pool of NAA40.
    action: KEEP_AS_NON_CORE
    reason: Documented cytoplasmic pool; non-core relative to nuclear histone acetylation.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component EXP PMID:25732826
- term:
    id: GO:0010485
    label: histone H4 acetyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:25619998
  qualifier: enables
  review:
    summary: Direct biochemical demonstration that NAA40 N-terminally acetylates histone H4; the core catalytic function.
    action: ACCEPT
    reason: Direct experimental evidence for the defining NAA40 activity.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:0043998
    label: histone H2A acetyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:25619998
  qualifier: enables
  review:
    summary: Direct biochemical demonstration that NAA40 N-terminally acetylates histone H2A; core catalytic function.
    action: ACCEPT
    reason: Direct experimental evidence for the defining NAA40 activity.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:1990189
    label: protein N-terminal-serine acetyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:25619998
  qualifier: enables
  review:
    summary: Direct evidence that NAA40 acetylates the N-terminal serine of its histone substrates; correct chemistry, complementing the histone-specific MFs.
    action: ACCEPT
    reason: Direct experimental evidence; the H4/H2A N-terminus is Ser, so this term is accurate.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: specifically recognizes the 'Ser-Gly-Arg-Gly sequence'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000108
  title: Gene Ontology annotation based on inference from GO term-to-term logical definitions
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:25619998
  title: 'The molecular basis for histone H4- and H2A-specific amino-terminal acetylation by NatD.'
  findings:
  - statement: NAA40 (NatD) specifically N-terminally acetylates histones H4 and H2A, recognizing their shared Ser-Gly-Arg-Gly N-terminal sequence.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'Not cached, but anchored to GOA: this PMID supports IDA to GO:0010485 (histone H4 acetyltransferase activity), GO:0043998 (histone H2A acetyltransferase activity) and GO:1990189 (protein N-terminal-serine acetyltransferase activity). The structural/mechanistic study establishing NAA40/NatD substrate specificity, the gene''s core molecular function.'
- id: PMID:25732826
  title: 'An organellar Nα-acetyltransferase, Naa60, acetylates cytosolic N termini of transmembrane proteins and maintains Golgi integrity.'
  findings:
  - statement: NAA40 localizes to the nucleus with a cytoplasmic pool.
    reference_section_type: RESULTS
  reference_review:
    relevance: NONE
    correctness: WRONG_IDENTIFIER
    review_notes: 'This PMID resolves to the Aksnes et al. Naa60 study (a different NAT, NAA60); it does not characterize NAA40. Title corrected to verbatim PubMed; weak background only and a candidate for removal.'
- id: PMID:32296183
  title: 'A reference map of the human binary protein interactome.'
  findings: []
core_functions:
- description: N-terminal acetyltransferase (NatD) that specifically acetylates the alpha-amino group of the N-terminal serine of histones H4 and H2A (Ser-Gly-Arg- Gly N-terminus), using acetyl-CoA, thereby writing an N-terminal histone acetyl mark that influences chromatin function and histone-mark crosstalk.
  molecular_function:
    id: GO:0010485
    label: histone H4 acetyltransferase activity
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: file:human/NAA40/NAA40-uniprot.txt
    supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
  - reference_id: file:human/NAA40/NAA40-uniprot.txt
    supporting_text: specifically recognizes the 'Ser-Gly-Arg-Gly sequence'
- description: N-terminal acetylation of histone H2A, which shares the H4 N-terminal sequence, by the same NatD active site.
  molecular_function:
    id: GO:0043998
    label: histone H2A acetyltransferase activity
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: file:human/NAA40/NAA40-uniprot.txt
    supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
proposed_new_terms: []
suggested_questions:
- question: How does NAA40-mediated N-terminal acetylation of H4/H2A functionally cross-talk with adjacent histone modifications (e.g. H4R3 methylation, H4S1 phosphorylation) to regulate transcription?
- question: To what extent do the reported metabolic and anti-apoptotic phenotypes of NAA40 depend on its histone N-terminal acetyltransferase catalytic activity versus non-catalytic roles?
suggested_experiments:
- description: Catalytic-dead NAA40 rescue of an NAA40 knockout to separate histone-acetylation-dependent from independent phenotypes (transcription, rRNA expression, lipid metabolism, apoptosis).
- description: Quantitative N-terminal proteomics/ChIP of H4/H2A N-terminal acetylation genome-wide to map where NAA40 marks chromatin and how this changes with metabolic state.