{"gene":"NAA30","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2003,"finding":"NAA30 (Mak3p) is the catalytic subunit of the NatC N-terminal acetyltransferase complex in yeast, which also contains auxiliary subunits Mak10p and Mak31p. NatC acetylates N-terminal sequences beginning with Met followed by a bulky hydrophobic residue.","method":"Biochemical characterization, phylogenetic analysis, substrate sequence analysis of >450 yeast proteins and >300 mammalian proteins","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — foundational biochemical characterization replicated across multiple studies and organisms, substrate profiles defined experimentally","pmids":["12507466","12890471"],"is_preprint":false},{"year":2008,"finding":"NatC (containing catalytic subunit Mak3p/NAA30) is associated with mono- and polyribosome fractions, indicating co-translational N-terminal acetylation activity at the ribosome.","method":"Biochemical fractionation in linear sucrose density gradients; TAP-affinity purification","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation with ribosome disruption controls, single lab but two orthogonal methods","pmids":["17541948"],"is_preprint":false},{"year":2016,"finding":"Human NAA30 (catalytic subunit of NatC) Nt-acetylates 46 substrates in vivo, including proteins with Met-Leu, Met-Ile, Met-Phe, Met-Trp, Met-Val, Met-Met, Met-His, and Met-Lys N-termini. Knockdown of Naa30 causes loss of mitochondrial membrane potential and mitochondrial fragmentation.","method":"Knockdown of NAA30 combined with positional proteomics (N-terminomics); mitochondrial membrane potential assay; fluorescence microscopy","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteome-wide substrate identification combined with functional cellular readouts, multiple orthogonal methods in one study","pmids":["27694331"],"is_preprint":false},{"year":2017,"finding":"Depletion of human NAA30 induces fragmentation of the Golgi apparatus and causes aberrant localization of ARFRP1 (a likely NatC substrate based on its N-terminal sequence) from cis-Golgi/TGN to non-Golgi vesicular structures, though membrane association of ARFRP1 is not lost.","method":"shRNA knockdown of hNaa30 in HeLa and CAL-62 cells; immunofluorescence microscopy of Golgi markers and ARFRP1","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (Golgi fragmentation) via knockdown, single lab","pmids":["28356483"],"is_preprint":false},{"year":2017,"finding":"A splice variant of human NAA30 (Naa30288) localizes predominantly to the nucleus in contrast to full-length Naa30 which is cytoplasmic. Full-length Naa30 acetylates a classical NatC substrate peptide in vitro, while Naa30288 shows no NAT activity. Neither form displays lysine acetyltransferase activity. Full-length Naa30 overexpression increases cell viability via inhibition of apoptosis, while Naa30288 does not.","method":"In vitro acetyltransferase assay with NatC substrate peptide; subcellular localization by fluorescence microscopy; cell viability and apoptosis assays; mutagenesis/isoform analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic assay plus localization and functional cell assays, multiple orthogonal methods, single lab","pmids":["29247799"],"is_preprint":false},{"year":2021,"finding":"Human NAA30 can functionally replace yeast Mak3p/Naa30 in rescuing growth phenotypes of mak3Δ yeast on non-fermentable carbon sources and under stress conditions, demonstrating evolutionary conservation of NatC function from yeast to human.","method":"Complementation assay — expression of human NAA30 in yeast mak3Δ strains; liquid growth assays under multiple stress conditions","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic complementation in two yeast strain backgrounds, functional rescue assay, single lab","pmids":["33600573"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of S. pombe NatC with a NatE/C-type bisubstrate analog and inositol hexaphosphate (IP6) reveals that all three subunits (Naa30 catalytic, Naa35 large auxiliary, Naa38 small auxiliary) are required for normal NatC acetylation activity, and IP6 binds tightly to NatC to stabilize the complex. The molecular basis for overlapping yet distinct substrate profiles of NatC and NatE was defined.","method":"Cryo-electron microscopy structure determination; biochemical acetyltransferase assays; mutagenesis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with biochemical assays and mutagenesis in one study, multiple orthogonal methods","pmids":["34019809"],"is_preprint":false},{"year":2022,"finding":"N-terminomics of yeast deleted for the NatC catalytic subunit Naa30 identified 57 yeast NatC substrates, expanding the canonical NatC substrate repertoire (ML, MI, MF, MW) to include MY, MK, MM, MA, MV, and MS N-termini, with evidence for redundancy between NatC and NatE/Naa50 for some substrate types. Human NAA30 expression rescued yeast NatC phenotypes and partially restored the yeast NatC Nt-acetylome.","method":"N-terminal combined fractional diagonal chromatography (N-TAILS/N-terminal COFRADIC) on naa30Δ yeast; genetic complementation with human NAA30","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — proteome-wide substrate identification by N-terminomics combined with genetic complementation, multiple orthogonal methods","pmids":["36567016"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of human NatC with and without NAA38 reveal that NAA38 increases the thermostability of the complex and broadens the substrate-specificity profile of NAA30 by ordering an N-terminal segment of NAA35 and reorienting an NAA30 N-terminal peptide-binding loop for optimal catalysis.","method":"Cryo-EM structure determination of human NatC ± NAA38; biochemical acetyltransferase assays; thermostability assays","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with biochemical validation and mutagenesis, multiple orthogonal methods in one study","pmids":["36638802"],"is_preprint":false},{"year":2015,"finding":"Knockdown of NAA30 (NAT12) in glioblastoma-initiating cells reduces cell viability, sphere-forming ability, and mitochondrial hypoxia tolerance, and prolongs animal survival after intracranial transplantation. NAA30 knockdown correlates with reduced HIF1α and phospho-mTOR(Ser2448) protein levels and increased p53 and GFAP levels.","method":"shRNA-mediated knockdown; cell viability assays; sphere formation assay; intracranial transplantation in SCID mice; Western blot; microarray","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple cellular and in vivo phenotypic readouts plus downstream protein analysis, single lab","pmids":["26292663"],"is_preprint":false},{"year":2026,"finding":"NAA30 is transcriptionally regulated by NR2C2 (which binds the NAA30 promoter and enhances its transcriptional activity). NAA30 binds ARPC1B protein (identified by IP-LC/MS) and Nt-acetylates ARPC1B; NAA30 knockdown enhances polyubiquitination of ARPC1B and promotes its proteasomal degradation. Re-expression of ARPC1B rescues malignant phenotypes in NAA30-silenced ovarian cancer cells.","method":"Dual-luciferase promoter assay; IP-LC/MS; N-terminal acetylation modification omics; co-immunoprecipitation; ubiquitination assay; rescue experiment by ARPC1B re-expression","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (IP-MS, ubiquitination assay, rescue experiment, promoter assay), single lab","pmids":["41615304"],"is_preprint":false},{"year":2026,"finding":"All three components of the NatC complex (Naa35, Naa38, and Naa30) were identified by genome-wide CRISPR screening as key molecules conferring resistance to ER stress in C2C12 myoblasts. NatC components are upregulated downstream of the ATF6 branch of the UPR; Naa35 knockdown reduces CTSK protein levels and prevents CTSK-mediated proteolysis of IRS1, preserving anabolic signaling and muscle mass in cancer cachexia mice.","method":"Genome-wide CRISPR screen; ATF6 inhibitor/activator treatment; shRNA knockdown via AAV in LLC tumor-bearing mice; Western blot; histology; grip strength and hanging assays","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen followed by in vivo functional validation, multiple methods, single lab; Naa30 role inferred from complex membership with primary mechanistic focus on Naa35","pmids":["41852114"],"is_preprint":false}],"current_model":"NAA30 is the catalytic subunit of the NatC N-terminal acetyltransferase complex (with auxiliary subunits NAA35 and NAA38), which co-translationally acetylates the N-termini of proteins bearing Met followed by bulky hydrophobic/amphipathic residues (ML, MI, MF, MW, and others) at the ribosome; structurally, NAA38 orders the NAA35 N-terminal segment and reorients an NAA30 peptide-binding loop to broaden substrate specificity and increase thermostability, while IP6 stabilizes the whole complex; functionally, NAA30-mediated acetylation is essential for mitochondrial integrity, Golgi organization (via ARFRP1 and ARPC1B localization/stability), and protection against ER stress-induced muscle wasting, with its transcription regulated by NR2C2 in cancer contexts."},"narrative":{"mechanistic_narrative":"NAA30 is the catalytic subunit of the NatC N-terminal acetyltransferase complex, which co-translationally acetylates protein N-termini at the ribosome [PMID:12507466, PMID:12890471, PMID:17541948]. Together with the auxiliary subunits NAA35 and NAA38, NAA30 acetylates substrates beginning with Met followed by a bulky hydrophobic or amphipathic residue, with proteome-wide N-terminomics defining a substrate repertoire spanning ML, MI, MF, MW, and additional MV/MM/MK/MY/MA/MS N-termini [PMID:27694331, PMID:36567016]. Structurally, NAA38 broadens NAA30 substrate specificity and increases complex thermostability by ordering the NAA35 N-terminal segment and reorienting an NAA30 peptide-binding loop, while inositol hexaphosphate (IP6) binds and stabilizes the assembled complex [PMID:34019809, PMID:36638802]. NAA30 activity is required for organellar integrity: its depletion collapses mitochondrial membrane potential and fragments mitochondria [PMID:27694331], and disperses the Golgi apparatus through mislocalization of the substrate ARFRP1 [PMID:28356483]. NAA30 N-terminally acetylates ARPC1B, protecting it from polyubiquitination and proteasomal degradation, a function exploited in ovarian cancer where NAA30 is transcriptionally driven by NR2C2 [PMID:41615304]. In glioblastoma-initiating cells, NAA30 supports viability, sphere formation, and hypoxia tolerance [PMID:26292663], and the NatC complex confers resistance to ER stress downstream of the ATF6 arm of the UPR, protecting against muscle wasting in cancer cachexia [PMID:41852114]. The full-length cytoplasmic enzyme, but not a catalytically inactive nuclear splice variant, possesses NAT activity and promotes cell survival [PMID:29247799].","teleology":[{"year":2003,"claim":"Established the foundational identity of NatC by showing NAA30 is the catalytic subunit acting with two auxiliary subunits and defining its Met-X substrate signature, framing all subsequent mechanistic work.","evidence":"Biochemical characterization and substrate sequence analysis of yeast Mak3p/NatC across hundreds of yeast and mammalian proteins","pmids":["12507466","12890471"],"confidence":"High","gaps":["Substrate scope defined by sequence inference, not exhaustive in vivo proteomics","Structural basis of catalysis and subunit cooperation unknown at this stage"]},{"year":2008,"claim":"Answered where NatC acts by localizing the complex to ribosomes, establishing co-translational acetylation as its mode of action.","evidence":"Sucrose density gradient fractionation and TAP-affinity purification in yeast","pmids":["17541948"],"confidence":"Medium","gaps":["Does not define which nascent chains are engaged co-translationally","Single lab; ribosome association in human cells not directly demonstrated here"]},{"year":2016,"claim":"Defined the human NAA30 substrate set in vivo and linked its activity to a concrete organellar phenotype, showing acetylation is required for mitochondrial integrity.","evidence":"NAA30 knockdown with positional proteomics, membrane potential assay, and fluorescence microscopy in human cells","pmids":["27694331"],"confidence":"High","gaps":["Which specific mitochondrial substrate(s) mediate the phenotype not pinpointed","Mechanism linking lost N-acetylation to membrane potential collapse unresolved"]},{"year":2017,"claim":"Extended NAA30 function to Golgi maintenance by identifying ARFRP1 as a likely substrate whose localization depends on NatC activity.","evidence":"shRNA knockdown in HeLa and CAL-62 cells with immunofluorescence of Golgi markers and ARFRP1","pmids":["28356483"],"confidence":"Medium","gaps":["Direct N-acetylation of ARFRP1 by NAA30 not demonstrated biochemically","ARFRP1 retains membrane association, so the molecular consequence of mislocalization is unclear"]},{"year":2017,"claim":"Distinguished NAT-active full-length NAA30 from an inactive nuclear splice variant, tying catalytic competence to subcellular localization and a pro-survival anti-apoptotic role.","evidence":"In vitro acetyltransferase assay, localization microscopy, and viability/apoptosis assays comparing Naa30 isoforms","pmids":["29247799"],"confidence":"Medium","gaps":["Physiological function of the nuclear variant unknown","Mechanism linking acetyltransferase activity to apoptosis inhibition not defined"]},{"year":2021,"claim":"Demonstrated functional conservation by showing human NAA30 rescues yeast mak3Δ phenotypes, validating cross-species use of yeast as a model for human NatC.","evidence":"Genetic complementation of yeast mak3Δ strains with human NAA30 and stress growth assays","pmids":["33600573"],"confidence":"Medium","gaps":["Rescue at growth level does not confirm identical substrate spectra across species","Single lab"]},{"year":2021,"claim":"Resolved the architecture of the trimeric complex, establishing that all three subunits are needed for activity and that IP6 is an integral stabilizing cofactor.","evidence":"Cryo-EM of S. pombe NatC with a bisubstrate analog and IP6, plus biochemical assays and mutagenesis","pmids":["34019809"],"confidence":"High","gaps":["Mechanism distinguishing NatC from NatE substrate preference only partially explained","Human complex structure not yet resolved at this point"]},{"year":2022,"claim":"Expanded the experimentally validated NatC substrate repertoire and revealed redundancy with NatE/Naa50 for certain N-termini, refining substrate boundaries.","evidence":"N-terminal COFRADIC on naa30Δ yeast with human NAA30 complementation","pmids":["36567016"],"confidence":"High","gaps":["Extent of NatC/NatE redundancy in human cells not quantified","Functional consequences of acetylating the newly identified substrates unknown"]},{"year":2023,"claim":"Mechanistically explained how the auxiliary subunit NAA38 tunes NAA30, showing it broadens substrate specificity and stabilizes the complex by reorganizing the catalytic peptide-binding loop.","evidence":"Cryo-EM of human NatC ± NAA38 with biochemical and thermostability assays","pmids":["36638802"],"confidence":"High","gaps":["Whether NAA38 occupancy is regulated in cells is unknown","In vivo substrate shifts attributable to NAA38 not mapped"]},{"year":2026,"claim":"Connected NAA30 acetylation to substrate protein stability and a cancer pathway, showing N-acetylation of ARPC1B prevents its degradation under NR2C2 transcriptional control.","evidence":"IP-LC/MS, N-acetylation omics, ubiquitination and rescue assays, and promoter luciferase assays in ovarian cancer cells","pmids":["41615304"],"confidence":"Medium","gaps":["Direct causal link between the specific acetyl mark and ubiquitin protection not isolated","Single lab; generality beyond ovarian cancer untested"]},{"year":2026,"claim":"Placed the NatC complex in the ER-stress/UPR response, identifying it as a determinant of ER stress resistance and muscle preservation in cachexia.","evidence":"Genome-wide CRISPR screen in C2C12 myoblasts with ATF6 modulation and in vivo AAV knockdown in tumor-bearing mice","pmids":["41852114"],"confidence":"Medium","gaps":["Primary mechanistic focus is on NAA35; NAA30-specific contribution inferred from complex membership","Which acetylated substrates mediate ER stress resistance not identified"]},{"year":null,"claim":"The molecular link between loss of N-terminal acetylation of specific substrates and the downstream organellar and disease phenotypes remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No substrate-resolved mechanism connecting acetylation loss to mitochondrial/Golgi collapse","Regulation of NAA30 activity in human tissues largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,4,6,7,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,7,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[11]}],"complexes":["NatC N-terminal acetyltransferase complex"],"partners":["NAA35","NAA38","ARFRP1","ARPC1B","NR2C2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q147X3","full_name":"N-alpha-acetyltransferase 30","aliases":["N-acetyltransferase 12","N-acetyltransferase MAK3 homolog","NatC catalytic subunit"],"length_aa":362,"mass_kda":39.3,"function":"Catalytic subunit of the N-terminal acetyltransferase C (NatC) complex (PubMed:19398576, PubMed:37891180). Catalyzes acetylation of the N-terminal methionine residues of peptides beginning with Met-Leu-Ala and Met-Leu-Gly (PubMed:19398576, PubMed:37891180). N-terminal acetylation protects proteins from ubiquitination and degradation by the N-end rule pathway (PubMed:37891180). Necessary for the lysosomal localization and function of ARL8B sugeesting that ARL8B is a NatC substrate (PubMed:19398576)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q147X3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NAA30","classification":"Not Classified","n_dependent_lines":253,"n_total_lines":1208,"dependency_fraction":0.20943708609271522},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NAA30","total_profiled":1310},"omim":[{"mim_id":"619438","title":"N-ALPHA-ACETYLTRANSFERASE 35, NatC AUXILIARY SUBUNIT; NAA35","url":"https://www.omim.org/entry/619438"},{"mim_id":"617990","title":"N-ALPHA-ACETYLTRANSFERASE 38, NatC AUXILIARY SUBUNIT; NAA38","url":"https://www.omim.org/entry/617990"},{"mim_id":"617989","title":"N-ALPHA-ACETYLTRANSFERASE 30, NatC CATALYTIC SUBUNIT; NAA30","url":"https://www.omim.org/entry/617989"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NAA30"},"hgnc":{"alias_symbol":["FLJ35355","MAK3","Mak3p"],"prev_symbol":["C14orf35","NAT12"]},"alphafold":{"accession":"Q147X3","domains":[{"cath_id":"3.40.630.30","chopping":"185-194_213-319","consensus_level":"medium","plddt":91.9114,"start":185,"end":319}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q147X3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q147X3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q147X3-F1-predicted_aligned_error_v6.png","plddt_mean":63.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NAA30","jax_strain_url":"https://www.jax.org/strain/search?query=NAA30"},"sequence":{"accession":"Q147X3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q147X3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q147X3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q147X3"}},"corpus_meta":[{"pmid":"12507466","id":"PMC_12507466","title":"N-terminal 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American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41615304","citation_count":0,"is_preprint":false},{"pmid":"42055348","id":"PMC_42055348","title":"Histone acetyltransferases and N-terminal acetyltransferases orchestrate development and metamorphosis in the yellow fever mosquito, Aedes aegypti.","date":"2026","source":"Insect biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/42055348","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21915,"output_tokens":3239,"usd":0.057165,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10680,"output_tokens":3589,"usd":0.071563,"stage2_stop_reason":"end_turn"},"total_usd":0.128728,"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\": 2003,\n      \"finding\": \"NAA30 (Mak3p) is the catalytic subunit of the NatC N-terminal acetyltransferase complex in yeast, which also contains auxiliary subunits Mak10p and Mak31p. NatC acetylates N-terminal sequences beginning with Met followed by a bulky hydrophobic residue.\",\n      \"method\": \"Biochemical characterization, phylogenetic analysis, substrate sequence analysis of >450 yeast proteins and >300 mammalian proteins\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — foundational biochemical characterization replicated across multiple studies and organisms, substrate profiles defined experimentally\",\n      \"pmids\": [\"12507466\", \"12890471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NatC (containing catalytic subunit Mak3p/NAA30) is associated with mono- and polyribosome fractions, indicating co-translational N-terminal acetylation activity at the ribosome.\",\n      \"method\": \"Biochemical fractionation in linear sucrose density gradients; TAP-affinity purification\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation with ribosome disruption controls, single lab but two orthogonal methods\",\n      \"pmids\": [\"17541948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human NAA30 (catalytic subunit of NatC) Nt-acetylates 46 substrates in vivo, including proteins with Met-Leu, Met-Ile, Met-Phe, Met-Trp, Met-Val, Met-Met, Met-His, and Met-Lys N-termini. Knockdown of Naa30 causes loss of mitochondrial membrane potential and mitochondrial fragmentation.\",\n      \"method\": \"Knockdown of NAA30 combined with positional proteomics (N-terminomics); mitochondrial membrane potential assay; fluorescence microscopy\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteome-wide substrate identification combined with functional cellular readouts, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27694331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Depletion of human NAA30 induces fragmentation of the Golgi apparatus and causes aberrant localization of ARFRP1 (a likely NatC substrate based on its N-terminal sequence) from cis-Golgi/TGN to non-Golgi vesicular structures, though membrane association of ARFRP1 is not lost.\",\n      \"method\": \"shRNA knockdown of hNaa30 in HeLa and CAL-62 cells; immunofluorescence microscopy of Golgi markers and ARFRP1\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (Golgi fragmentation) via knockdown, single lab\",\n      \"pmids\": [\"28356483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A splice variant of human NAA30 (Naa30288) localizes predominantly to the nucleus in contrast to full-length Naa30 which is cytoplasmic. Full-length Naa30 acetylates a classical NatC substrate peptide in vitro, while Naa30288 shows no NAT activity. Neither form displays lysine acetyltransferase activity. Full-length Naa30 overexpression increases cell viability via inhibition of apoptosis, while Naa30288 does not.\",\n      \"method\": \"In vitro acetyltransferase assay with NatC substrate peptide; subcellular localization by fluorescence microscopy; cell viability and apoptosis assays; mutagenesis/isoform analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic assay plus localization and functional cell assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"29247799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human NAA30 can functionally replace yeast Mak3p/Naa30 in rescuing growth phenotypes of mak3Δ yeast on non-fermentable carbon sources and under stress conditions, demonstrating evolutionary conservation of NatC function from yeast to human.\",\n      \"method\": \"Complementation assay — expression of human NAA30 in yeast mak3Δ strains; liquid growth assays under multiple stress conditions\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation in two yeast strain backgrounds, functional rescue assay, single lab\",\n      \"pmids\": [\"33600573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of S. pombe NatC with a NatE/C-type bisubstrate analog and inositol hexaphosphate (IP6) reveals that all three subunits (Naa30 catalytic, Naa35 large auxiliary, Naa38 small auxiliary) are required for normal NatC acetylation activity, and IP6 binds tightly to NatC to stabilize the complex. The molecular basis for overlapping yet distinct substrate profiles of NatC and NatE was defined.\",\n      \"method\": \"Cryo-electron microscopy structure determination; biochemical acetyltransferase assays; mutagenesis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with biochemical assays and mutagenesis in one study, multiple orthogonal methods\",\n      \"pmids\": [\"34019809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"N-terminomics of yeast deleted for the NatC catalytic subunit Naa30 identified 57 yeast NatC substrates, expanding the canonical NatC substrate repertoire (ML, MI, MF, MW) to include MY, MK, MM, MA, MV, and MS N-termini, with evidence for redundancy between NatC and NatE/Naa50 for some substrate types. Human NAA30 expression rescued yeast NatC phenotypes and partially restored the yeast NatC Nt-acetylome.\",\n      \"method\": \"N-terminal combined fractional diagonal chromatography (N-TAILS/N-terminal COFRADIC) on naa30Δ yeast; genetic complementation with human NAA30\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — proteome-wide substrate identification by N-terminomics combined with genetic complementation, multiple orthogonal methods\",\n      \"pmids\": [\"36567016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of human NatC with and without NAA38 reveal that NAA38 increases the thermostability of the complex and broadens the substrate-specificity profile of NAA30 by ordering an N-terminal segment of NAA35 and reorienting an NAA30 N-terminal peptide-binding loop for optimal catalysis.\",\n      \"method\": \"Cryo-EM structure determination of human NatC ± NAA38; biochemical acetyltransferase assays; thermostability assays\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with biochemical validation and mutagenesis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36638802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockdown of NAA30 (NAT12) in glioblastoma-initiating cells reduces cell viability, sphere-forming ability, and mitochondrial hypoxia tolerance, and prolongs animal survival after intracranial transplantation. NAA30 knockdown correlates with reduced HIF1α and phospho-mTOR(Ser2448) protein levels and increased p53 and GFAP levels.\",\n      \"method\": \"shRNA-mediated knockdown; cell viability assays; sphere formation assay; intracranial transplantation in SCID mice; Western blot; microarray\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple cellular and in vivo phenotypic readouts plus downstream protein analysis, single lab\",\n      \"pmids\": [\"26292663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NAA30 is transcriptionally regulated by NR2C2 (which binds the NAA30 promoter and enhances its transcriptional activity). NAA30 binds ARPC1B protein (identified by IP-LC/MS) and Nt-acetylates ARPC1B; NAA30 knockdown enhances polyubiquitination of ARPC1B and promotes its proteasomal degradation. Re-expression of ARPC1B rescues malignant phenotypes in NAA30-silenced ovarian cancer cells.\",\n      \"method\": \"Dual-luciferase promoter assay; IP-LC/MS; N-terminal acetylation modification omics; co-immunoprecipitation; ubiquitination assay; rescue experiment by ARPC1B re-expression\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (IP-MS, ubiquitination assay, rescue experiment, promoter assay), single lab\",\n      \"pmids\": [\"41615304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"All three components of the NatC complex (Naa35, Naa38, and Naa30) were identified by genome-wide CRISPR screening as key molecules conferring resistance to ER stress in C2C12 myoblasts. NatC components are upregulated downstream of the ATF6 branch of the UPR; Naa35 knockdown reduces CTSK protein levels and prevents CTSK-mediated proteolysis of IRS1, preserving anabolic signaling and muscle mass in cancer cachexia mice.\",\n      \"method\": \"Genome-wide CRISPR screen; ATF6 inhibitor/activator treatment; shRNA knockdown via AAV in LLC tumor-bearing mice; Western blot; histology; grip strength and hanging assays\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen followed by in vivo functional validation, multiple methods, single lab; Naa30 role inferred from complex membership with primary mechanistic focus on Naa35\",\n      \"pmids\": [\"41852114\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NAA30 is the catalytic subunit of the NatC N-terminal acetyltransferase complex (with auxiliary subunits NAA35 and NAA38), which co-translationally acetylates the N-termini of proteins bearing Met followed by bulky hydrophobic/amphipathic residues (ML, MI, MF, MW, and others) at the ribosome; structurally, NAA38 orders the NAA35 N-terminal segment and reorients an NAA30 peptide-binding loop to broaden substrate specificity and increase thermostability, while IP6 stabilizes the whole complex; functionally, NAA30-mediated acetylation is essential for mitochondrial integrity, Golgi organization (via ARFRP1 and ARPC1B localization/stability), and protection against ER stress-induced muscle wasting, with its transcription regulated by NR2C2 in cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NAA30 is the catalytic subunit of the NatC N-terminal acetyltransferase complex, which co-translationally acetylates protein N-termini at the ribosome [#0, #1]. Together with the auxiliary subunits NAA35 and NAA38, NAA30 acetylates substrates beginning with Met followed by a bulky hydrophobic or amphipathic residue, with proteome-wide N-terminomics defining a substrate repertoire spanning ML, MI, MF, MW, and additional MV/MM/MK/MY/MA/MS N-termini [#2, #7]. Structurally, NAA38 broadens NAA30 substrate specificity and increases complex thermostability by ordering the NAA35 N-terminal segment and reorienting an NAA30 peptide-binding loop, while inositol hexaphosphate (IP6) binds and stabilizes the assembled complex [#6, #8]. NAA30 activity is required for organellar integrity: its depletion collapses mitochondrial membrane potential and fragments mitochondria [#2], and disperses the Golgi apparatus through mislocalization of the substrate ARFRP1 [#3]. NAA30 N-terminally acetylates ARPC1B, protecting it from polyubiquitination and proteasomal degradation, a function exploited in ovarian cancer where NAA30 is transcriptionally driven by NR2C2 [#10]. In glioblastoma-initiating cells, NAA30 supports viability, sphere formation, and hypoxia tolerance [#9], and the NatC complex confers resistance to ER stress downstream of the ATF6 arm of the UPR, protecting against muscle wasting in cancer cachexia [#11]. The full-length cytoplasmic enzyme, but not a catalytically inactive nuclear splice variant, possesses NAT activity and promotes cell survival [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the foundational identity of NatC by showing NAA30 is the catalytic subunit acting with two auxiliary subunits and defining its Met-X substrate signature, framing all subsequent mechanistic work.\",\n      \"evidence\": \"Biochemical characterization and substrate sequence analysis of yeast Mak3p/NatC across hundreds of yeast and mammalian proteins\",\n      \"pmids\": [\"12507466\", \"12890471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate scope defined by sequence inference, not exhaustive in vivo proteomics\", \"Structural basis of catalysis and subunit cooperation unknown at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Answered where NatC acts by localizing the complex to ribosomes, establishing co-translational acetylation as its mode of action.\",\n      \"evidence\": \"Sucrose density gradient fractionation and TAP-affinity purification in yeast\",\n      \"pmids\": [\"17541948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define which nascent chains are engaged co-translationally\", \"Single lab; ribosome association in human cells not directly demonstrated here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the human NAA30 substrate set in vivo and linked its activity to a concrete organellar phenotype, showing acetylation is required for mitochondrial integrity.\",\n      \"evidence\": \"NAA30 knockdown with positional proteomics, membrane potential assay, and fluorescence microscopy in human cells\",\n      \"pmids\": [\"27694331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific mitochondrial substrate(s) mediate the phenotype not pinpointed\", \"Mechanism linking lost N-acetylation to membrane potential collapse unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended NAA30 function to Golgi maintenance by identifying ARFRP1 as a likely substrate whose localization depends on NatC activity.\",\n      \"evidence\": \"shRNA knockdown in HeLa and CAL-62 cells with immunofluorescence of Golgi markers and ARFRP1\",\n      \"pmids\": [\"28356483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct N-acetylation of ARFRP1 by NAA30 not demonstrated biochemically\", \"ARFRP1 retains membrane association, so the molecular consequence of mislocalization is unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished NAT-active full-length NAA30 from an inactive nuclear splice variant, tying catalytic competence to subcellular localization and a pro-survival anti-apoptotic role.\",\n      \"evidence\": \"In vitro acetyltransferase assay, localization microscopy, and viability/apoptosis assays comparing Naa30 isoforms\",\n      \"pmids\": [\"29247799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological function of the nuclear variant unknown\", \"Mechanism linking acetyltransferase activity to apoptosis inhibition not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated functional conservation by showing human NAA30 rescues yeast mak3\\u0394 phenotypes, validating cross-species use of yeast as a model for human NatC.\",\n      \"evidence\": \"Genetic complementation of yeast mak3\\u0394 strains with human NAA30 and stress growth assays\",\n      \"pmids\": [\"33600573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Rescue at growth level does not confirm identical substrate spectra across species\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the architecture of the trimeric complex, establishing that all three subunits are needed for activity and that IP6 is an integral stabilizing cofactor.\",\n      \"evidence\": \"Cryo-EM of S. pombe NatC with a bisubstrate analog and IP6, plus biochemical assays and mutagenesis\",\n      \"pmids\": [\"34019809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing NatC from NatE substrate preference only partially explained\", \"Human complex structure not yet resolved at this point\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded the experimentally validated NatC substrate repertoire and revealed redundancy with NatE/Naa50 for certain N-termini, refining substrate boundaries.\",\n      \"evidence\": \"N-terminal COFRADIC on naa30\\u0394 yeast with human NAA30 complementation\",\n      \"pmids\": [\"36567016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Extent of NatC/NatE redundancy in human cells not quantified\", \"Functional consequences of acetylating the newly identified substrates unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mechanistically explained how the auxiliary subunit NAA38 tunes NAA30, showing it broadens substrate specificity and stabilizes the complex by reorganizing the catalytic peptide-binding loop.\",\n      \"evidence\": \"Cryo-EM of human NatC \\u00b1 NAA38 with biochemical and thermostability assays\",\n      \"pmids\": [\"36638802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NAA38 occupancy is regulated in cells is unknown\", \"In vivo substrate shifts attributable to NAA38 not mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected NAA30 acetylation to substrate protein stability and a cancer pathway, showing N-acetylation of ARPC1B prevents its degradation under NR2C2 transcriptional control.\",\n      \"evidence\": \"IP-LC/MS, N-acetylation omics, ubiquitination and rescue assays, and promoter luciferase assays in ovarian cancer cells\",\n      \"pmids\": [\"41615304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct causal link between the specific acetyl mark and ubiquitin protection not isolated\", \"Single lab; generality beyond ovarian cancer untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed the NatC complex in the ER-stress/UPR response, identifying it as a determinant of ER stress resistance and muscle preservation in cachexia.\",\n      \"evidence\": \"Genome-wide CRISPR screen in C2C12 myoblasts with ATF6 modulation and in vivo AAV knockdown in tumor-bearing mice\",\n      \"pmids\": [\"41852114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primary mechanistic focus is on NAA35; NAA30-specific contribution inferred from complex membership\", \"Which acetylated substrates mediate ER stress resistance not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular link between loss of N-terminal acetylation of specific substrates and the downstream organellar and disease phenotypes remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate-resolved mechanism connecting acetylation loss to mitochondrial/Golgi collapse\", \"Regulation of NAA30 activity in human tissues largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 4, 6, 7, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 7, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\"NatC N-terminal acetyltransferase complex\"],\n    \"partners\": [\"NAA35\", \"NAA38\", \"ARFRP1\", \"ARPC1B\", \"NR2C2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}