{"gene":"NAT14","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2000,"finding":"Human KLP1 (NAT14) protein binds specifically to the coproporphyrinogen oxidase promoter regulatory element (CPRE; sequence GGACTACAG) and acts as a DNA sequence-specific transcription factor that activates transcription from CPRE-containing promoters. The protein contains a leucine-zipper-like structure, a Leu-X-X-Leu-Leu motif, and a putative nuclear localization signal.","method":"Southwestern screening of K562 cDNA library, gel mobility shift assay (EMSA), transfection/reporter assay in THP-1 cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus reporter assay in a single lab, two orthogonal methods establishing DNA binding and transcriptional activation","pmids":["10873651"],"is_preprint":false},{"year":2001,"finding":"The human KLP1 (NAT14) gene spans ~2.4 kb with three exons; its promoter contains multiple GC boxes, an E2F binding site, a CRE at -42, and no TATA box. The CRE at -42 is essential for full promoter activity, and c-Jun and ATF1/CREB1 proteins bind this element. Promoter activity is higher in serum-stimulated (cycling) K562 cells than in quiescent cells, consistent with a role in cell cycle regulation.","method":"Genomic sequencing, promoter deletion analysis, reporter assay, electrophoretic mobility shift assay with c-Jun/ATF1/CREB1","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis combined with EMSA identifying specific binding proteins, single lab","pmids":["11779635"],"is_preprint":false},{"year":2023,"finding":"NAT14 forms a trimeric transcriptional complex with the micropeptide MOXI and transcription factor c-Jun. This MOXI/NAT14/c-Jun complex enhances basal and TGF-β1-induced collagen I gene promoter activity. Complex formation requires phosphorylation of MOXI at T49, which is also required for MOXI nuclear translocation. The interaction was identified by bimolecular fluorescence complementation.","method":"Bimolecular fluorescence complementation (BiFC), reporter assay (collagen I promoter-luciferase), point mutation (T49A MOXI knockin mouse), antisense oligonucleotide knockdown, mouse fibrosis models (folic acid and unilateral ureteral obstruction)","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BiFC interaction assay plus functional reporter assay plus in vivo genetic validation (T49A knockin), single lab but multiple orthogonal methods","pmids":["36804379"],"is_preprint":false},{"year":2009,"finding":"NAT14 was tested for N-acetyltransferase activity toward L-aspartate and acetyl-CoA (NAA synthesis) by transfection in HEK-293T cells; NAT14 did NOT catalyze NAA synthesis, whereas its paralog NAT8L did. This is a negative result establishing that NAT14 lacks aspartate N-acetyltransferase activity.","method":"Transfection in HEK-293T cells with enzymatic assay for NAA synthesis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct enzymatic activity assay in a cell-based system; negative result for NAT14, single lab","pmids":["19807691"],"is_preprint":false}],"current_model":"Human NAT14 (KLP1) is a nuclear protein that functions as a DNA sequence-specific transcription factor binding the CPRE element (GGACTACAG) to activate gene transcription; its promoter is regulated by c-Jun/ATF1/CREB1 and cell-cycle status; NAT14 also participates in a trimeric transcriptional complex with the micropeptide MOXI and c-Jun to drive fibrotic gene (collagen I) expression, a complex dependent on MOXI phosphorylation at T49; NAT14 does not possess aspartate N-acetyltransferase activity."},"narrative":{"mechanistic_narrative":"NAT14 (KLP1) is a nuclear sequence-specific DNA-binding transcription factor that activates target gene expression [PMID:10873651]. It binds the coproporphyrinogen oxidase promoter regulatory element (CPRE, GGACTACAG) through a protein bearing a leucine-zipper-like structure and a Leu-X-X-Leu-Leu motif, and stimulates transcription from CPRE-containing promoters [PMID:10873651]. The NAT14 gene is itself a cell-cycle-responsive transcriptional unit: its TATA-less promoter depends on a CRE element at -42 bound by c-Jun and ATF1/CREB1, and promoter activity is elevated in cycling versus quiescent cells [PMID:11779635]. Beyond autonomous DNA binding, NAT14 acts within a trimeric transcriptional complex together with the micropeptide MOXI and c-Jun, where MOXI phosphorylation at T49 drives its nuclear translocation and complex assembly to enhance basal and TGF-β1-induced collagen I promoter activity, linking NAT14 to fibrotic gene expression [PMID:36804379]. Despite its name, NAT14 does not possess aspartate N-acetyltransferase activity, in contrast to its paralog NAT8L [PMID:19807691].","teleology":[{"year":2000,"claim":"Established that NAT14/KLP1 is not merely a sequence-named protein but a functional sequence-specific transcription factor, defining its DNA target and activator role.","evidence":"Southwestern cDNA library screening, EMSA, and reporter assay identifying CPRE (GGACTACAG) binding and transcriptional activation in THP-1 cells","pmids":["10873651"],"confidence":"Medium","gaps":["Genome-wide target repertoire beyond the CPRE element not defined","Structural basis of DNA recognition by the leucine-zipper-like motif not resolved","Single-lab characterization without independent replication"]},{"year":2001,"claim":"Resolved how NAT14 expression is itself controlled, placing the gene downstream of CRE-binding factors and cell-cycle status.","evidence":"Genomic sequencing, promoter deletion/mutagenesis, reporter assays, and EMSA with c-Jun/ATF1/CREB1 in K562 cells","pmids":["11779635"],"confidence":"Medium","gaps":["Functional consequence of cell-cycle-dependent NAT14 expression on downstream targets not demonstrated","Role of the E2F site and GC boxes not functionally dissected"]},{"year":2009,"claim":"Excluded a presumptive enzymatic function, showing NAT14 lacks the aspartate N-acetyltransferase activity of its paralog and forcing its role to be understood through transcription rather than acetylation.","evidence":"Transfection in HEK-293T cells with enzymatic NAA-synthesis assay; negative for NAT14, positive for NAT8L","pmids":["19807691"],"confidence":"Medium","gaps":["Negative result does not exclude acetyltransferase activity toward other substrates","No catalytic activity of any kind positively assigned to NAT14"]},{"year":2023,"claim":"Extended NAT14 function from autonomous DNA binding to a defined multiprotein transcriptional module, linking it mechanistically to fibrotic gene programs.","evidence":"BiFC interaction assay, collagen I promoter reporter, MOXI T49A knockin mouse, antisense knockdown, and folic acid/UUO fibrosis models","pmids":["36804379"],"confidence":"Medium","gaps":["Direct NAT14-c-Jun and NAT14-MOXI binding interfaces not mapped","Whether NAT14 contacts the collagen I promoter DNA directly within the complex not established","Single-lab study"]},{"year":null,"claim":"How NAT14's CPRE-binding activity, cell-cycle-regulated expression, and MOXI/c-Jun complex function integrate into a unified regulatory program remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of NAT14 or its DNA-binding mode","Genome-wide target genes and physiological output beyond collagen I unknown","Mechanism connecting CPRE/heme-pathway regulation to fibrotic gene control not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2]}],"complexes":["MOXI/NAT14/c-Jun transcriptional complex"],"partners":["MOXI","JUN","ATF1","CREB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WUY8","full_name":"Probable N-acetyltransferase 14","aliases":["K562 cell-derived leucine-zipper-like protein 1"],"length_aa":206,"mass_kda":21.6,"function":"Probable acetyltransferase May act as a transcription factor that regulates the expression of coproporphyrinogen oxidase by binding to a promoter regulatory element","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q8WUY8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NAT14","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NAT14","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":66.2}],"url":"https://www.proteinatlas.org/search/NAT14"},"hgnc":{"alias_symbol":["KLP1"],"prev_symbol":[]},"alphafold":{"accession":"Q8WUY8","domains":[{"cath_id":"3.40.630.30","chopping":"2-206","consensus_level":"medium","plddt":83.553,"start":2,"end":206}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUY8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUY8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUY8-F1-predicted_aligned_error_v6.png","plddt_mean":83.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NAT14","jax_strain_url":"https://www.jax.org/strain/search?query=NAT14"},"sequence":{"accession":"Q8WUY8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUY8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUY8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUY8"}},"corpus_meta":[{"pmid":"17296796","id":"PMC_17296796","title":"Chlamydomonas reinhardtii hydin is a central pair protein required for flagellar motility.","date":"2007","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17296796","citation_count":119,"is_preprint":false},{"pmid":"9295136","id":"PMC_9295136","title":"The role of central apparatus components in flagellar motility and microtubule assembly.","date":"1997","source":"Cell motility and the cytoskeleton","url":"https://pubmed.ncbi.nlm.nih.gov/9295136","citation_count":112,"is_preprint":false},{"pmid":"19807691","id":"PMC_19807691","title":"Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia.","date":"2009","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/19807691","citation_count":102,"is_preprint":false},{"pmid":"8207060","id":"PMC_8207060","title":"A new kinesin-like protein (Klp1) localized to a single microtubule of the Chlamydomonas flagellum.","date":"1994","source":"The Journal of cell 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neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15715087","citation_count":28,"is_preprint":false},{"pmid":"36804379","id":"PMC_36804379","title":"Mitochondrial micropeptide MOXI promotes fibrotic gene transcription by translocation to the nucleus and bridging N-acetyltransferase 14 with transcription factor c-Jun.","date":"2023","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/36804379","citation_count":14,"is_preprint":false},{"pmid":"10873651","id":"PMC_10873651","title":"Cloning of a coproporphyrinogen oxidase promoter regulatory element binding protein.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10873651","citation_count":14,"is_preprint":false},{"pmid":"29336910","id":"PMC_29336910","title":"Bioconversion of hemicellulosic materials into ethanol by yeast, Pichia kudriavzevii 2-KLP1, isolated from industrial waste.","date":"2018","source":"Revista Argentina de microbiologia","url":"https://pubmed.ncbi.nlm.nih.gov/29336910","citation_count":13,"is_preprint":false},{"pmid":"31497230","id":"PMC_31497230","title":"Molecular mechanisms involved in TGF-β1-induced Muscle-derived stem cells differentiation to smooth muscle cells.","date":"2019","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/31497230","citation_count":9,"is_preprint":false},{"pmid":"38258067","id":"PMC_38258067","title":"Maximizing Anticancer Response with MPS1 and CENPE Inhibition Alongside Apoptosis Induction.","date":"2023","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/38258067","citation_count":8,"is_preprint":false},{"pmid":"11779635","id":"PMC_11779635","title":"Genomic structure and regulation of a novel human gene, Klp1.","date":"2001","source":"Biochimica et biophysica 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apparatus.","date":"2007","source":"Protoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/18157500","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10818,"output_tokens":1218,"usd":0.025362,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7805,"output_tokens":1938,"usd":0.043737,"stage2_stop_reason":"end_turn"},"total_usd":0.069099,"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\": 2000,\n      \"finding\": \"Human KLP1 (NAT14) protein binds specifically to the coproporphyrinogen oxidase promoter regulatory element (CPRE; sequence GGACTACAG) and acts as a DNA sequence-specific transcription factor that activates transcription from CPRE-containing promoters. The protein contains a leucine-zipper-like structure, a Leu-X-X-Leu-Leu motif, and a putative nuclear localization signal.\",\n      \"method\": \"Southwestern screening of K562 cDNA library, gel mobility shift assay (EMSA), transfection/reporter assay in THP-1 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus reporter assay in a single lab, two orthogonal methods establishing DNA binding and transcriptional activation\",\n      \"pmids\": [\"10873651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The human KLP1 (NAT14) gene spans ~2.4 kb with three exons; its promoter contains multiple GC boxes, an E2F binding site, a CRE at -42, and no TATA box. The CRE at -42 is essential for full promoter activity, and c-Jun and ATF1/CREB1 proteins bind this element. Promoter activity is higher in serum-stimulated (cycling) K562 cells than in quiescent cells, consistent with a role in cell cycle regulation.\",\n      \"method\": \"Genomic sequencing, promoter deletion analysis, reporter assay, electrophoretic mobility shift assay with c-Jun/ATF1/CREB1\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis combined with EMSA identifying specific binding proteins, single lab\",\n      \"pmids\": [\"11779635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAT14 forms a trimeric transcriptional complex with the micropeptide MOXI and transcription factor c-Jun. This MOXI/NAT14/c-Jun complex enhances basal and TGF-β1-induced collagen I gene promoter activity. Complex formation requires phosphorylation of MOXI at T49, which is also required for MOXI nuclear translocation. The interaction was identified by bimolecular fluorescence complementation.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC), reporter assay (collagen I promoter-luciferase), point mutation (T49A MOXI knockin mouse), antisense oligonucleotide knockdown, mouse fibrosis models (folic acid and unilateral ureteral obstruction)\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BiFC interaction assay plus functional reporter assay plus in vivo genetic validation (T49A knockin), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36804379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NAT14 was tested for N-acetyltransferase activity toward L-aspartate and acetyl-CoA (NAA synthesis) by transfection in HEK-293T cells; NAT14 did NOT catalyze NAA synthesis, whereas its paralog NAT8L did. This is a negative result establishing that NAT14 lacks aspartate N-acetyltransferase activity.\",\n      \"method\": \"Transfection in HEK-293T cells with enzymatic assay for NAA synthesis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic activity assay in a cell-based system; negative result for NAT14, single lab\",\n      \"pmids\": [\"19807691\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human NAT14 (KLP1) is a nuclear protein that functions as a DNA sequence-specific transcription factor binding the CPRE element (GGACTACAG) to activate gene transcription; its promoter is regulated by c-Jun/ATF1/CREB1 and cell-cycle status; NAT14 also participates in a trimeric transcriptional complex with the micropeptide MOXI and c-Jun to drive fibrotic gene (collagen I) expression, a complex dependent on MOXI phosphorylation at T49; NAT14 does not possess aspartate N-acetyltransferase activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NAT14 (KLP1) is a nuclear sequence-specific DNA-binding transcription factor that activates target gene expression [#0]. It binds the coproporphyrinogen oxidase promoter regulatory element (CPRE, GGACTACAG) through a protein bearing a leucine-zipper-like structure and a Leu-X-X-Leu-Leu motif, and stimulates transcription from CPRE-containing promoters [#0]. The NAT14 gene is itself a cell-cycle-responsive transcriptional unit: its TATA-less promoter depends on a CRE element at -42 bound by c-Jun and ATF1/CREB1, and promoter activity is elevated in cycling versus quiescent cells [#1]. Beyond autonomous DNA binding, NAT14 acts within a trimeric transcriptional complex together with the micropeptide MOXI and c-Jun, where MOXI phosphorylation at T49 drives its nuclear translocation and complex assembly to enhance basal and TGF-\\u03b21-induced collagen I promoter activity, linking NAT14 to fibrotic gene expression [#2]. Despite its name, NAT14 does not possess aspartate N-acetyltransferase activity, in contrast to its paralog NAT8L [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that NAT14/KLP1 is not merely a sequence-named protein but a functional sequence-specific transcription factor, defining its DNA target and activator role.\",\n      \"evidence\": \"Southwestern cDNA library screening, EMSA, and reporter assay identifying CPRE (GGACTACAG) binding and transcriptional activation in THP-1 cells\",\n      \"pmids\": [\"10873651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genome-wide target repertoire beyond the CPRE element not defined\",\n        \"Structural basis of DNA recognition by the leucine-zipper-like motif not resolved\",\n        \"Single-lab characterization without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved how NAT14 expression is itself controlled, placing the gene downstream of CRE-binding factors and cell-cycle status.\",\n      \"evidence\": \"Genomic sequencing, promoter deletion/mutagenesis, reporter assays, and EMSA with c-Jun/ATF1/CREB1 in K562 cells\",\n      \"pmids\": [\"11779635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of cell-cycle-dependent NAT14 expression on downstream targets not demonstrated\",\n        \"Role of the E2F site and GC boxes not functionally dissected\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Excluded a presumptive enzymatic function, showing NAT14 lacks the aspartate N-acetyltransferase activity of its paralog and forcing its role to be understood through transcription rather than acetylation.\",\n      \"evidence\": \"Transfection in HEK-293T cells with enzymatic NAA-synthesis assay; negative for NAT14, positive for NAT8L\",\n      \"pmids\": [\"19807691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Negative result does not exclude acetyltransferase activity toward other substrates\",\n        \"No catalytic activity of any kind positively assigned to NAT14\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended NAT14 function from autonomous DNA binding to a defined multiprotein transcriptional module, linking it mechanistically to fibrotic gene programs.\",\n      \"evidence\": \"BiFC interaction assay, collagen I promoter reporter, MOXI T49A knockin mouse, antisense knockdown, and folic acid/UUO fibrosis models\",\n      \"pmids\": [\"36804379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct NAT14-c-Jun and NAT14-MOXI binding interfaces not mapped\",\n        \"Whether NAT14 contacts the collagen I promoter DNA directly within the complex not established\",\n        \"Single-lab study\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NAT14's CPRE-binding activity, cell-cycle-regulated expression, and MOXI/c-Jun complex function integrate into a unified regulatory program remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of NAT14 or its DNA-binding mode\",\n        \"Genome-wide target genes and physiological output beyond collagen I unknown\",\n        \"Mechanism connecting CPRE/heme-pathway regulation to fibrotic gene control not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"MOXI/NAT14/c-Jun transcriptional complex\"],\n    \"partners\": [\"MOXI\", \"JUN\", \"ATF1\", \"CREB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}