{"gene":"NAA38","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2021,"finding":"The NatC complex requires all three subunits (Naa30, Naa35, Naa38) for normal N-terminal acetyltransferase activity in yeast; cryo-EM structure of S. pombe NatC with a NatE/C-type bisubstrate analog revealed that inositol hexaphosphate (IP6) binds tightly to NatC to stabilize the complex.","method":"Cryo-EM structure determination, biochemical activity assays, bisubstrate analog co-crystallization","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional biochemistry, multiple orthogonal methods in one study","pmids":["34019809"],"is_preprint":false},{"year":2023,"finding":"NAA38 increases the thermostability of human NatC and broadens its substrate-specificity profile by (1) ordering an N-terminal segment of NAA35 and (2) reorienting an NAA30 N-terminal peptide-binding loop for optimal catalysis, as revealed by cryo-EM structures of hNatC with and without NAA38 together with biochemical studies.","method":"Cryo-EM structure determination of hNatC ±NAA38, biochemical thermostability and substrate-specificity assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures combined with biochemical assays directly attributing thermostability and substrate-broadening to NAA38, multiple orthogonal methods in one rigorous study","pmids":["36638802"],"is_preprint":false},{"year":2017,"finding":"NAA38 is an auxiliary subunit of the NatC complex (together with catalytic Naa30 and auxiliary Naa35); full-length Naa30 acetylates classical NatC substrate peptides in vitro and the NatC complex acts co-translationally at the ribosome.","method":"In vitro N-terminal acetyltransferase activity assay with peptide substrates; complex subunit characterization","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro activity assay with NatC subunit context; single lab, but consistent with structural studies","pmids":["29247799"],"is_preprint":false},{"year":2019,"finding":"Disruption of NAA38 leads to stabilization of the transcription factor NRF2 (via a KEAP1-NRF2 pathway), increasing intracellular glutathione levels; however, this only weakly protects cells from ferroptosis, in part because NRF2 concomitantly upregulates MRP1-mediated glutathione efflux.","method":"Genome-wide haploid genetic screen coupled with FACS-based sorting for glutathione levels; ferroptosis viability assays","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide genetic screen with phenotypic validation; pathway placement via epistasis but mechanistic link to NAA38 itself is indirect (loss-of-function screen)","pmids":["30726737"],"is_preprint":false},{"year":2026,"finding":"CRISPR screening identified Naa38 (together with Naa35 and Naa30, all three NatC subunits) as a key molecule conferring resistance to ER stress in muscle cells; NatC activity is upregulated by ATF6-branch UPR signaling, and NatC promotes muscle atrophy in cancer cachexia by sustaining cathepsin K (CTSK) protein levels, which drives proteolysis of insulin receptor substrate 1.","method":"Genome-wide CRISPR screen in ER-stress context; shRNA knockdown in vivo (mouse LLC cancer cachexia model); western blotting; ATF6 inhibitor/activator pharmacology","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus in vivo KD with defined molecular pathway (CTSK→IRS1 proteolysis); mechanistic attribution to NAA38 specifically is partial since phenotype is attributed to whole NatC complex","pmids":["41852114"],"is_preprint":false}],"current_model":"NAA38 is the small auxiliary subunit of the trimeric NatC N-terminal acetyltransferase complex; structurally, it orders the NAA35 N-terminal segment and reorients the NAA30 substrate-binding loop to increase thermostability and broaden substrate specificity, while the entire three-subunit complex (stabilized by inositol hexaphosphate) is required for full co-translational N-terminal acetylation activity; loss of NAA38 function also indirectly stabilizes NRF2 to elevate glutathione, and NatC activity is induced by ATF6-branch ER stress to promote muscle catabolism via cathepsin K."},"narrative":{"mechanistic_narrative":"NAA38 is the small auxiliary subunit of the trimeric NatC N-terminal acetyltransferase complex, which acts co-translationally at the ribosome together with the catalytic subunit NAA30 and the auxiliary subunit NAA35 to acetylate the N-termini of substrate proteins [PMID:34019809, PMID:29247799]. All three subunits are required for full NatC activity, and the assembled complex is stabilized by tightly bound inositol hexaphosphate (IP6) [PMID:34019809]. Structurally, NAA38 contributes to catalytic competence by ordering an N-terminal segment of NAA35 and reorienting an NAA30 peptide-binding loop, which increases the thermostability of human NatC and broadens its substrate-specificity profile [PMID:36638802]. Beyond its core acetyltransferase role, loss of NAA38 function stabilizes the transcription factor NRF2 through the KEAP1-NRF2 pathway and raises intracellular glutathione, although this only weakly protects against ferroptosis because NRF2 also drives MRP1-mediated glutathione efflux [PMID:30726737]. NatC activity is induced by ATF6-branch ER stress and, through sustaining cathepsin K (CTSK) protein levels that drive proteolysis of insulin receptor substrate 1, promotes muscle atrophy in cancer cachexia [PMID:41852114].","teleology":[{"year":2017,"claim":"Established NAA38 as an auxiliary subunit of the NatC complex and placed its activity in the co-translational N-terminal acetylation context, defining the functional unit within which NAA38 operates.","evidence":"In vitro N-terminal acetyltransferase activity assays with peptide substrates and NatC subunit characterization","pmids":["29247799"],"confidence":"Medium","gaps":["Does not resolve the specific structural contribution of NAA38 versus the catalytic NAA30 subunit","Single-lab in vitro characterization without structural detail"]},{"year":2019,"claim":"Connected NAA38 loss to redox homeostasis, showing that disruption stabilizes NRF2 and elevates glutathione, linking the acetyltransferase machinery to ferroptosis sensitivity.","evidence":"Genome-wide haploid genetic screen with FACS sorting for glutathione and ferroptosis viability assays","pmids":["30726737"],"confidence":"Medium","gaps":["Mechanistic link to NAA38 is indirect, derived from a loss-of-function screen rather than a defined molecular intermediate","How NatC activity feeds into the KEAP1-NRF2 axis is not defined","Does not identify the NatC substrate(s) responsible for the phenotype"]},{"year":2021,"claim":"Resolved the architecture of NatC and showed all three subunits are required for normal activity, while identifying IP6 as a structural cofactor stabilizing the complex.","evidence":"Cryo-EM structure of S. pombe NatC with a bisubstrate analog plus biochemical activity assays","pmids":["34019809"],"confidence":"High","gaps":["Performed in S. pombe; the specific role of NAA38 within the human complex was not isolated","Functional consequence of IP6 binding for catalysis not fully dissected"]},{"year":2023,"claim":"Directly attributed thermostabilization and substrate-specificity broadening of human NatC to NAA38 by comparing structures with and without the subunit, defining its mechanistic contribution.","evidence":"Cryo-EM structures of human NatC ±NAA38 with thermostability and substrate-specificity biochemical assays","pmids":["36638802"],"confidence":"High","gaps":["Full repertoire of substrates broadened by NAA38 in vivo not enumerated","Cellular consequences of NAA38-dependent substrate broadening not established"]},{"year":2026,"claim":"Linked NatC activity to ER-stress resistance and cancer cachexia, showing ATF6-branch UPR induces NatC, which sustains cathepsin K to drive IRS1 proteolysis and muscle atrophy.","evidence":"Genome-wide CRISPR screen in ER-stress context, in vivo shRNA knockdown in a mouse LLC cachexia model, western blotting, and ATF6 pharmacology","pmids":["41852114"],"confidence":"Medium","gaps":["Phenotype attributed to the whole NatC complex rather than NAA38 specifically","Whether cathepsin K stabilization depends on direct N-terminal acetylation is not established","Mechanism by which ATF6 signaling upregulates NatC is undefined"]},{"year":null,"claim":"The in vivo substrate repertoire of NAA38-containing NatC and the causal chain linking its acetyltransferase activity to the NRF2/glutathione and cathepsin K phenotypes remain to be defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No NatC substrate has been mechanistically tied to either the ferroptosis or cachexia phenotype","Whether the downstream effects are acetylation-dependent is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]}],"complexes":["NatC complex"],"partners":["NAA30","NAA35"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BRA0","full_name":"N-alpha-acetyltransferase 38, NatC auxiliary subunit","aliases":["LSM domain-containing protein 1","Phosphonoformate immuno-associated protein 2"],"length_aa":125,"mass_kda":13.5,"function":"Auxillary component of the N-terminal acetyltransferase C (NatC) complex which catalyzes acetylation of N-terminal methionine residues (PubMed:19398576, PubMed:37891180). N-terminal acetylation protects proteins from ubiquitination and degradation by the N-end rule pathway (PubMed:37891180)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BRA0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NAA38","classification":"Not Classified","n_dependent_lines":42,"n_total_lines":1208,"dependency_fraction":0.0347682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NAA38","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":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NAA38"},"hgnc":{"alias_symbol":["MGC14151","PFAAP2"],"prev_symbol":["LSMD1"]},"alphafold":{"accession":"Q9BRA0","domains":[{"cath_id":"2.30.30.100","chopping":"48-115","consensus_level":"high","plddt":93.2072,"start":48,"end":115}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRA0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRA0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRA0-F1-predicted_aligned_error_v6.png","plddt_mean":78.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NAA38","jax_strain_url":"https://www.jax.org/strain/search?query=NAA38"},"sequence":{"accession":"Q9BRA0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BRA0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BRA0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRA0"}},"corpus_meta":[{"pmid":"30726737","id":"PMC_30726737","title":"A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30726737","citation_count":182,"is_preprint":false},{"pmid":"26474971","id":"PMC_26474971","title":"A genome-wide approach to link genotype to clinical outcome by utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients.","date":"2015","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26474971","citation_count":70,"is_preprint":false},{"pmid":"29247799","id":"PMC_29247799","title":"Identification of an alternatively spliced nuclear isoform of human N-terminal acetyltransferase Naa30.","date":"2017","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29247799","citation_count":14,"is_preprint":false},{"pmid":"34019809","id":"PMC_34019809","title":"Molecular mechanism of N-terminal acetylation by the ternary NatC complex.","date":"2021","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/34019809","citation_count":12,"is_preprint":false},{"pmid":"36638802","id":"PMC_36638802","title":"Molecular role of NAA38 in thermostability and catalytic activity of the human NatC N-terminal acetyltransferase.","date":"2023","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/36638802","citation_count":9,"is_preprint":false},{"pmid":"27075776","id":"PMC_27075776","title":"A de novo interstitial deletion of 7q31.2q31.31 identified in a girl with developmental delay and hearing loss.","date":"2016","source":"American journal of medical genetics. Part C, Seminars in medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27075776","citation_count":9,"is_preprint":false},{"pmid":"33600573","id":"PMC_33600573","title":"Human NAA30 can rescue yeast mak3∆ mutant growth phenotypes.","date":"2021","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/33600573","citation_count":5,"is_preprint":false},{"pmid":"41090760","id":"PMC_41090760","title":"Conditional ATXN2L-Null in Adult Frontal Cortex CamK2a+ Neurons Does Not Cause Cell Death but Restricts Spontaneous Mobility and Affects the Alternative Splicing Pathway.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41090760","citation_count":3,"is_preprint":false},{"pmid":"41299435","id":"PMC_41299435","title":"Immune cell-based transcriptomic Mendelian randomization and colocalization study on type 1 diabetes.","date":"2025","source":"BMC medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41299435","citation_count":0,"is_preprint":false},{"pmid":"41852114","id":"PMC_41852114","title":"Inhibition of N-Terminal Acetyltransferase C Mitigates Endoplasmic Reticulum Stress-Mediated Muscle Atrophy in Cancer Cachexia.","date":"2026","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/41852114","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7316,"output_tokens":1390,"usd":0.021399,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8037,"output_tokens":2200,"usd":0.047593,"stage2_stop_reason":"end_turn"},"total_usd":0.068992,"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\": 2021,\n      \"finding\": \"The NatC complex requires all three subunits (Naa30, Naa35, Naa38) for normal N-terminal acetyltransferase activity in yeast; cryo-EM structure of S. pombe NatC with a NatE/C-type bisubstrate analog revealed that inositol hexaphosphate (IP6) binds tightly to NatC to stabilize the complex.\",\n      \"method\": \"Cryo-EM structure determination, biochemical activity assays, bisubstrate analog co-crystallization\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional biochemistry, multiple orthogonal methods in one study\",\n      \"pmids\": [\"34019809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAA38 increases the thermostability of human NatC and broadens its substrate-specificity profile by (1) ordering an N-terminal segment of NAA35 and (2) reorienting an NAA30 N-terminal peptide-binding loop for optimal catalysis, as revealed by cryo-EM structures of hNatC with and without NAA38 together with biochemical studies.\",\n      \"method\": \"Cryo-EM structure determination of hNatC ±NAA38, biochemical thermostability and substrate-specificity assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures combined with biochemical assays directly attributing thermostability and substrate-broadening to NAA38, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"36638802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NAA38 is an auxiliary subunit of the NatC complex (together with catalytic Naa30 and auxiliary Naa35); full-length Naa30 acetylates classical NatC substrate peptides in vitro and the NatC complex acts co-translationally at the ribosome.\",\n      \"method\": \"In vitro N-terminal acetyltransferase activity assay with peptide substrates; complex subunit characterization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro activity assay with NatC subunit context; single lab, but consistent with structural studies\",\n      \"pmids\": [\"29247799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Disruption of NAA38 leads to stabilization of the transcription factor NRF2 (via a KEAP1-NRF2 pathway), increasing intracellular glutathione levels; however, this only weakly protects cells from ferroptosis, in part because NRF2 concomitantly upregulates MRP1-mediated glutathione efflux.\",\n      \"method\": \"Genome-wide haploid genetic screen coupled with FACS-based sorting for glutathione levels; ferroptosis viability assays\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide genetic screen with phenotypic validation; pathway placement via epistasis but mechanistic link to NAA38 itself is indirect (loss-of-function screen)\",\n      \"pmids\": [\"30726737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CRISPR screening identified Naa38 (together with Naa35 and Naa30, all three NatC subunits) as a key molecule conferring resistance to ER stress in muscle cells; NatC activity is upregulated by ATF6-branch UPR signaling, and NatC promotes muscle atrophy in cancer cachexia by sustaining cathepsin K (CTSK) protein levels, which drives proteolysis of insulin receptor substrate 1.\",\n      \"method\": \"Genome-wide CRISPR screen in ER-stress context; shRNA knockdown in vivo (mouse LLC cancer cachexia model); western blotting; ATF6 inhibitor/activator pharmacology\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus in vivo KD with defined molecular pathway (CTSK→IRS1 proteolysis); mechanistic attribution to NAA38 specifically is partial since phenotype is attributed to whole NatC complex\",\n      \"pmids\": [\"41852114\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NAA38 is the small auxiliary subunit of the trimeric NatC N-terminal acetyltransferase complex; structurally, it orders the NAA35 N-terminal segment and reorients the NAA30 substrate-binding loop to increase thermostability and broaden substrate specificity, while the entire three-subunit complex (stabilized by inositol hexaphosphate) is required for full co-translational N-terminal acetylation activity; loss of NAA38 function also indirectly stabilizes NRF2 to elevate glutathione, and NatC activity is induced by ATF6-branch ER stress to promote muscle catabolism via cathepsin K.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NAA38 is the small auxiliary subunit of the trimeric NatC N-terminal acetyltransferase complex, which acts co-translationally at the ribosome together with the catalytic subunit NAA30 and the auxiliary subunit NAA35 to acetylate the N-termini of substrate proteins [#0, #2]. All three subunits are required for full NatC activity, and the assembled complex is stabilized by tightly bound inositol hexaphosphate (IP6) [#0]. Structurally, NAA38 contributes to catalytic competence by ordering an N-terminal segment of NAA35 and reorienting an NAA30 peptide-binding loop, which increases the thermostability of human NatC and broadens its substrate-specificity profile [#1]. Beyond its core acetyltransferase role, loss of NAA38 function stabilizes the transcription factor NRF2 through the KEAP1-NRF2 pathway and raises intracellular glutathione, although this only weakly protects against ferroptosis because NRF2 also drives MRP1-mediated glutathione efflux [#3]. NatC activity is induced by ATF6-branch ER stress and, through sustaining cathepsin K (CTSK) protein levels that drive proteolysis of insulin receptor substrate 1, promotes muscle atrophy in cancer cachexia [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established NAA38 as an auxiliary subunit of the NatC complex and placed its activity in the co-translational N-terminal acetylation context, defining the functional unit within which NAA38 operates.\",\n      \"evidence\": \"In vitro N-terminal acetyltransferase activity assays with peptide substrates and NatC subunit characterization\",\n      \"pmids\": [\"29247799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not resolve the specific structural contribution of NAA38 versus the catalytic NAA30 subunit\",\n        \"Single-lab in vitro characterization without structural detail\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected NAA38 loss to redox homeostasis, showing that disruption stabilizes NRF2 and elevates glutathione, linking the acetyltransferase machinery to ferroptosis sensitivity.\",\n      \"evidence\": \"Genome-wide haploid genetic screen with FACS sorting for glutathione and ferroptosis viability assays\",\n      \"pmids\": [\"30726737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link to NAA38 is indirect, derived from a loss-of-function screen rather than a defined molecular intermediate\",\n        \"How NatC activity feeds into the KEAP1-NRF2 axis is not defined\",\n        \"Does not identify the NatC substrate(s) responsible for the phenotype\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the architecture of NatC and showed all three subunits are required for normal activity, while identifying IP6 as a structural cofactor stabilizing the complex.\",\n      \"evidence\": \"Cryo-EM structure of S. pombe NatC with a bisubstrate analog plus biochemical activity assays\",\n      \"pmids\": [\"34019809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Performed in S. pombe; the specific role of NAA38 within the human complex was not isolated\",\n        \"Functional consequence of IP6 binding for catalysis not fully dissected\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Directly attributed thermostabilization and substrate-specificity broadening of human NatC to NAA38 by comparing structures with and without the subunit, defining its mechanistic contribution.\",\n      \"evidence\": \"Cryo-EM structures of human NatC \\u00b1NAA38 with thermostability and substrate-specificity biochemical assays\",\n      \"pmids\": [\"36638802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full repertoire of substrates broadened by NAA38 in vivo not enumerated\",\n        \"Cellular consequences of NAA38-dependent substrate broadening not established\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked NatC activity to ER-stress resistance and cancer cachexia, showing ATF6-branch UPR induces NatC, which sustains cathepsin K to drive IRS1 proteolysis and muscle atrophy.\",\n      \"evidence\": \"Genome-wide CRISPR screen in ER-stress context, in vivo shRNA knockdown in a mouse LLC cachexia model, western blotting, and ATF6 pharmacology\",\n      \"pmids\": [\"41852114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Phenotype attributed to the whole NatC complex rather than NAA38 specifically\",\n        \"Whether cathepsin K stabilization depends on direct N-terminal acetylation is not established\",\n        \"Mechanism by which ATF6 signaling upregulates NatC is undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo substrate repertoire of NAA38-containing NatC and the causal chain linking its acetyltransferase activity to the NRF2/glutathione and cathepsin K phenotypes remain to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No NatC substrate has been mechanistically tied to either the ferroptosis or cachexia phenotype\",\n        \"Whether the downstream effects are acetylation-dependent is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\"NatC complex\"],\n    \"partners\": [\"NAA30\", \"NAA35\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}