Affinage

NAA40

N-alpha-acetyltransferase 40 · UniProt Q86UY6

Length
237 aa
Mass
27.2 kDa
Annotated
2026-06-10
9 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NAA40 (NatD) is a histone-specific N-terminal acetyltransferase that acts co-translationally at the ribosomal peptide tunnel exit, where cryo-EM shows it coordinates with the Nascent polypeptide-Associated Complex (NAC) for ribosome binding and with METAP1 in a multienzyme arrangement that couples N-terminal methionine removal to acetylation of histones H4 and H2A (PMID:41820326). Beyond canonical H4 and H2A, NAA40 specifically interacts with and N-terminally acetylates the histone variant H2A.X, a dynamic modification that responds to UVB-induced DNA damage and influences cell survival (PMID:40665417). This N-terminal acetylation acts as a master switch over downstream histone marks: it prevents enrichment of repressive H2A/H4S1 phosphorylation and sustains PRMT5-dependent symmetric arginine methylation (H4R3me2s), forming an epistatic link between NAA40 acetylation and arginine methylation (PMID:30858358, PMID:34785778, PMID:40020320). Through this chromatin control, NAA40 drives transcriptional programs governing one-carbon and methionine-cycle metabolism and thymidylate synthase (TYMS) expression, conferring 5-FU chemoresistance (PMID:34785778), regulates the downstream target AGR2 (PMID:40020320), and constrains intracellular acetyl-CoA levels and de novo lipogenesis in hepatocytes (PMID:35057804). NAA40 depletion activates the mitochondrial caspase-9 intrinsic apoptotic cascade in a p53-independent manner (PMID:26666750), and NAA40 protein abundance is negatively controlled by RNF112-mediated ubiquitin-dependent proteasomal degradation within the KLF4-RNF112 axis (PMID:39757327).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2016 Medium

    Establishing that NAA40 is required for cancer cell survival placed it functionally upstream of the intrinsic apoptotic machinery rather than as an incidental modifier.

    Evidence siRNA knockdown in HCT116 and HT-29 CRC cells with caspase-9 activity assays and caspase-9 inhibitor rescue, including p53-null controls

    PMID:26666750

    Open questions at the time
    • Does not connect the survival phenotype to NAA40's catalytic histone acetylation activity
    • Mechanism linking histone modification to caspase-9 activation unresolved
  2. 2019 Medium

    Defining N-terminal acetylation of histone H4 serine 1 and its control of PRMT5 expression revealed that NAA40 acetylation governs a downstream arginine-methylation axis.

    Evidence NAA40 knockdown in CRC cells measuring H4R3me2s, PRMT5 levels, and xenograft growth

    PMID:30858358

    Open questions at the time
    • Whether PRMT5 downregulation is direct or secondary to chromatin changes not fully resolved
    • Single lab, single cancer context
  3. 2021 Medium

    Linking NAA40 to one-carbon metabolism showed that the acetylation mark actively prevents repressive H2A/H4S1 phosphorylation to keep metabolic genes such as TYMS transcribed, explaining a chemoresistance phenotype.

    Evidence Transcriptomic/metabolomic profiling, chromatin fractionation showing H2A/H4S1ph redistribution, and xenograft chemoresistance assays in CRC

    PMID:34785778

    Open questions at the time
    • Direct chromatin occupancy of NAA40 at metabolic gene promoters not shown
    • How acetylation antagonizes S1 phosphorylation mechanistically unclear
  4. 2022 Medium

    Showing that NAA40 loss raises acetyl-CoA and drives lipogenesis extended its role beyond cancer to systemic metabolic homeostasis, conserved from mouse hepatocytes to Drosophila.

    Evidence Metabolomics, lipidomics, lipogenesis gene expression and glucose uptake in NAA40-depleted hepatocytes plus Drosophila fat body assay

    PMID:35057804

    Open questions at the time
    • Causal chain from histone acetylation to acetyl-CoA accumulation not delineated
    • Insulin-independent lipid droplet mechanism unexplained
  5. 2025 Medium

    Identifying AGR2 as a downstream transcriptional target connected NAA40-dependent histone mark balance (H4S1ph, H4R3me2a/s, H3K4me3/H3K27me3) at a specific promoter to a phenocopying effector gene in osteosarcoma.

    Evidence ChIP-qPCR for histone marks at AGR2 promoter, luciferase reporter, and AGR2 rescue/knockdown with xenograft validation

    PMID:40020320

    Open questions at the time
    • Only partial rescue by AGR2 indicates additional effectors
    • Generality beyond osteosarcoma not tested
  6. 2025 Medium

    Demonstrating that RNF112 ubiquitinates and degrades NAA40 defined a post-translational control point and embedded NAA40 in the KLF4-RNF112 tumor-suppressive axis.

    Evidence Co-IP, ubiquitination assays, and NAA40 overexpression rescue in RNF112-overexpressing CRC cells with nude mouse tumor assays

    PMID:39757327

    Open questions at the time
    • Ubiquitination site(s) on NAA40 not mapped
    • Single Co-IP context for the RNF112-NAA40 interaction
  7. 2025 High

    Establishing direct N-terminal acetylation of histone variant H2A.X and its DNA-damage responsiveness expanded NAA40's substrate range and tied it to the genotoxic stress response.

    Evidence In vitro acetyltransferase assays, mass spectrometry detection of Nt-acH2A.X in cells, Co-IP, and UVB survival assays

    PMID:40665417

    Open questions at the time
    • How H2A.X N-terminal acetylation is dynamically removed/regulated not defined
    • Functional consequence for DNA repair signaling not mechanistically resolved
  8. 2026 High

    Solving the cryo-EM structure of NAA40 on the ribosome resolved how it achieves co-translational, histone-specific acetylation by coordinating with NAC and METAP1, providing the molecular basis for its substrate engagement.

    Evidence Cryo-EM structure with biochemical acetyltransferase and ribosome binding assays demonstrating the NAA40-NAC interaction requirement

    PMID:41820326

    Open questions at the time
    • Structural basis for nuclear (non-ribosomal) NAA40 activity not addressed
    • Relative contributions of co-translational vs post-translational acetylation in vivo unquantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The nuclear interactome and non-ribosomal functions of NAA40 remain to be defined and connected to its established chromatin and metabolic roles.
  • Single AP-MS dataset without validation of individual interactions
  • No functional role assigned to nuclear NAA40 partners
  • Whether nuclear NAA40 acetylates non-histone substrates unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0042393 histone binding 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 1 GO:0005840 ribosome 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-1430728 Metabolism 2 R-HSA-392499 Metabolism of proteins 1 R-HSA-5357801 Programmed Cell Death 1
Partners
H2AFXMETAP1NACRNF112
Complex memberships
ribosome-associated NAA40-NAC co-translational complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 NAA40 catalyzes N-terminal acetylation of histone H4 serine 1 (N-acH4); loss of NAA40 and N-acH4 reduces H4R3me2s levels through transcriptional downregulation of PRMT5, establishing a functional epistatic link between NAA40-mediated histone acetylation and PRMT5-dependent arginine methylation. NAA40 knockdown in CRC cells with measurement of H4R3me2s, PRMT5 mRNA/protein levels, and xenograft tumor growth assays Cell death & disease Medium 30858358
2016 Depletion of NAA40 in colorectal cancer cells activates the mitochondrial caspase-9-mediated apoptotic cascade in a p53-independent manner; treatment with an irreversible caspase-9 inhibitor blocks apoptosis induced by NAA40 knockdown, placing NAA40 upstream of the intrinsic apoptosis pathway. siRNA knockdown of NAA40 in HCT116 and HT-29 CRC cells (including p53-null HCT116), caspase-9 activity assays, caspase-9 inhibitor rescue experiments Apoptosis : an international journal on programmed cell death Medium 26666750
2021 NAA40 regulates one-carbon metabolism by controlling expression of the methionine cycle genes and thymidylate synthase (TYMS); mechanistically, NAA40 acetyltransferase activity prevents enrichment of repressive H2A/H4S1ph at the nuclear periphery, thereby activating TYMS transcription and promoting resistance to 5-FU chemotherapy. Transcriptomic and metabolomic analysis in CRC cells after NAA40 depletion; chromatin fractionation showing H2A/H4S1ph redistribution; in vitro and xenograft chemoresistance assays Oncogene Medium 34785778
2022 Depletion of NAA40 in murine hepatocytes leads to increased intracellular acetyl-CoA levels, which associates with enhanced de novo lipogenesis (upregulation of lipogenesis genes, increased diglycerides/triglycerides, cytoplasmic lipid droplet accumulation) and impaired insulin signalling (decreased glucose uptake); the effect on lipid droplet formation is independent of insulin. This effect is replicated in vivo in Drosophila larval fat body. Metabolomic and lipidomic analysis in NAA40-depleted murine hepatocytes; de novo lipogenesis gene expression; glucose uptake assay; Drosophila in vivo lipid droplet assay BMC biology Medium 35057804
2025 RNF112 E3 ubiquitin ligase promotes ubiquitin-dependent proteasomal degradation of NAA40 protein; overexpression of NAA40 rescues the anti-tumor effects of RNF112 overexpression in CRC, placing NAA40 downstream of the KLF4-RNF112 axis. Co-immunoprecipitation, ubiquitination assays, NAA40 overexpression rescue experiments in RNF112-overexpressing CRC cells, in vivo nude mouse tumor formation assay Cell biology and toxicology Medium 39757327
2025 NAA40 loss in osteosarcoma cells is associated with increased H4S1ph and H4R3me2a and decreased H4R3me2s, and leads to altered H3K4me3 and H3K27me3 at the AGR2 promoter, reducing AGR2 transcription; AGR2 is identified as a downstream transcriptional target of NAA40 and its knockdown phenocopies NAA40 loss, while AGR2 overexpression partially rescues NAA40-depletion phenotypes. ChIP-qPCR for histone marks at AGR2 promoter, dual luciferase reporter assay, rescue experiments with AGR2 overexpression, in vivo xenograft assay Biochemical and biophysical research communications Medium 40020320
2025 NAA40 specifically interacts with and N-terminally acetylates histone variant H2A.X (in vitro and in cells); H2A.X N-terminal acetylation is a dynamic modification responsive to UVB-induced DNA damage, and NAA40 affects cell survival upon UVB irradiation. In silico sequence analysis, biochemical acetyltransferase assays, mass spectrometry detection of Nt-acH2A.X in human cells, Co-IP of NAA40 with H2A.X, UVB cell survival assays Epigenetics & chromatin High 40665417
2026 NAA40 (NatD) acts co-translationally at the ribosomal peptide tunnel exit; cryo-EM structure shows NAA40 coordinates with the Nascent polypeptide-Associated Complex (NAC) for ribosome binding and efficient histone H2A/H4 N-terminal acetylation. The NAA40-NAC interaction is required for efficient ribosome binding and histone acetylation. A multienzyme complex on the ribosome involving METAP1 coordinates methionine removal with subsequent NAA40-mediated acetylation. Cryo-EM structural determination, biochemical acetyltransferase assays, ribosome binding assays, demonstration that NAA40-NAC interaction is required for histone acetylation Nature communications High 41820326
2025 Affinity purification–mass spectrometry (AP-MS) of NAA40 in the nuclear compartment identifies nuclear protein interaction partners of NAA40, consistent with NAA40 acting within the nucleus in addition to its co-translational ribosome-associated role. Affinity purification coupled to mass spectrometry (AP-MS) of nuclear NAA40 Methods in enzymology Low 40992843

Source papers

Stage 0 corpus · 9 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 NAA40 contributes to colorectal cancer growth by controlling PRMT5 expression. Cell death & disease 52 30858358
2016 Depletion of histone N-terminal-acetyltransferase Naa40 induces p53-independent apoptosis in colorectal cancer cells via the mitochondrial pathway. Apoptosis : an international journal on programmed cell death 45 26666750
2021 Histone N-terminal acetyltransferase NAA40 links one-carbon metabolism to chemoresistance. Oncogene 25 34785778
2022 Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis. BMC biology 23 35057804
2025 RNF112, whose transcription is regulated by KLF4, inhibits colorectal cancer growth via promoting ubiquitin-dependent degradation of NAA40. Cell biology and toxicology 4 39757327
2025 N-terminal histone acetyltransferase NAA40 modulates osteosarcoma progression by controlling AGR2 expression. Biochemical and biophysical research communications 2 40020320
2025 H2A.X N-terminal acetylation is a newly identified NAA40-mediated modification that is responsive to UV irradiation. Epigenetics & chromatin 2 40665417
2026 NAA40 and NAC cooperate in co-translational histone acetylation in humans. Nature communications 0 41820326
2025 Affinity purification-mass spectrometry to identify nuclear protein interactions of N-terminal acetyltransferase NAA40. Methods in enzymology 0 40992843

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