{"gene":"NAP1L4","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1997,"finding":"Recombinant NAP1L4 (NAP-2) protein interacts with both core and linker histones and can transfer histones onto naked DNA templates in vitro, demonstrating histone chaperone activity. Deletion mutagenesis showed that both NH2- and COOH-terminal domains are required for this histone transfer activity.","method":"In vitro histone binding and transfer assays with recombinant protein purified from E. coli; deletion mutagenesis","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of histone transfer activity combined with deletion mutagenesis defining functional domains, single lab but multiple orthogonal methods","pmids":["9325046"],"is_preprint":false},{"year":1997,"finding":"NAP1L4 (NAP-2) shuttles between the cytoplasm and the nucleus, consistent with a role as a histone chaperone delivering histones to the nucleus.","method":"Subcellular localization studies (fractionation/imaging of recombinant NAP-2)","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment in single lab; functional link inferred but consistent with in vitro chaperone data","pmids":["9325046"],"is_preprint":false},{"year":2019,"finding":"NAP1L4 knockdown increases Lys320 acetylation of p53 and enhances expression of the pro-arrest gene p21, thereby suppressing cell growth under normal conditions. Under genotoxic stress, NAP1L4 knockdown decreases Lys382 acetylation of p53 and attenuates proapoptotic Bax levels, suppressing apoptosis. These results indicate NAP1L4 modulates cell fate by controlling site-specific p53 acetylation.","method":"siRNA knockdown of NAP1L4 in mammalian cells, western blot for p53 acetylation at specific lysines (K320, K382), and measurement of p21 and Bax expression levels","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean knockdown with defined molecular readouts (site-specific p53 acetylation), single lab, single method type","pmids":["31634504"],"is_preprint":false},{"year":2021,"finding":"NAP1L4 (and NAP1L1) binds to the hypervariable domain (HVD) of Chikungunya virus nsP3 at two motifs located upstream and downstream of the G3BP-binding motifs. This interaction requires CK2 kinase-mediated phosphorylation of the HVD and has a strong stimulatory effect on CHIKV replication in vertebrate cells.","method":"Co-immunoprecipitation, binding assays, phosphorylation-dependency experiments with CK2 kinase inhibition/mutation, viral replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays with phosphorylation requirement defined, functional viral replication readout, single lab but multiple orthogonal approaches","pmids":["34076483"],"is_preprint":false},{"year":2020,"finding":"NAP1L4 directly interacts with porcine circovirus type 2 (PCV2) capsid protein (Cap) via NAP1L4 residues 124–279. Overexpression of NAP1L4 inhibits PCV2 Cap and Rep expression and reduces viral DNA copies and titers, while CRISPR/Cas9 knockout of NAP1L4 increases viral replication. Mechanistically, NAP1L4 depletion facilitates CCP5 and CCP6 expression, which activates cGAS to promote IFN-β production, and IFN-β stimulation promotes PCV2 replication.","method":"Co-IP to map interaction domain; NAP1L4 overexpression and CRISPR/Cas9 knockout in PK15 cells; qRT-PCR and western blot for viral and IFN-β markers; viral titer measurement","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping by deletion, genetic KO and OE with defined molecular pathway (cGAS-IFN-β), single lab, multiple orthogonal methods","pmids":["32605741"],"is_preprint":false},{"year":2024,"finding":"NAP1L4 is a prenylated protein in human cardiac cells. Prenylation of NAP1L4 regulates cardiomyocyte mitosis and centrosome homeostasis, as shown by chemical and genetic perturbation of the mevalonate/prenylation pathway in human pluripotent stem cell-derived cardiomyocytes.","method":"Prenyl probe labeling and mass spectrometry identification; chemical inhibition and genetic perturbation of prenylation; cardiomyocyte proliferation and centrosome assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, prenylation identified by chemical probe/MS with functional readout but limited mechanistic detail in abstract","pmids":["bio_10.1101_2024.07.01.601625"],"is_preprint":true}],"current_model":"NAP1L4 is a histone chaperone that binds core and linker histones and transfers them onto DNA via both its N- and C-terminal domains, shuttling between cytoplasm and nucleus; it also modulates p53 acetylation at specific lysines (K320, K382) to regulate cell fate decisions, interacts with viral proteins (CHIKV nsP3 HVD in a phosphorylation-dependent manner, and PCV2 Cap) to influence viral replication, and undergoes prenylation that controls cardiomyocyte mitosis and centrosome homeostasis."},"narrative":{"mechanistic_narrative":"NAP1L4 is a histone chaperone that binds both core and linker histones and transfers them onto naked DNA, an activity requiring both its N- and C-terminal domains [PMID:9325046], and it shuttles between cytoplasm and nucleus consistent with delivering histones into the nucleus [PMID:9325046]. Beyond chromatin assembly, NAP1L4 regulates cell fate by controlling site-specific p53 acetylation: its loss raises Lys320 acetylation and the pro-arrest target p21 under normal conditions while lowering Lys382 acetylation and the proapoptotic factor Bax under genotoxic stress [PMID:31634504]. NAP1L4 is also exploited or countered by viruses — it binds the phosphorylated hypervariable domain of Chikungunya virus nsP3 (a CK2-dependent interaction) to stimulate viral replication [PMID:34076483], and it directly binds the porcine circovirus 2 capsid protein through residues 124–279, restricting replication by suppressing a CCP5/CCP6–cGAS–IFN-β axis [PMID:32605741].","teleology":[{"year":1997,"claim":"Established NAP1L4 as a bona fide histone chaperone by showing it both binds histones and deposits them onto DNA, and mapped this activity to two terminal domains.","evidence":"In vitro histone binding and transfer assays with recombinant protein plus deletion mutagenesis","pmids":["9325046"],"confidence":"High","gaps":["No structural model of the histone-binding interface","In vitro deposition does not establish which histones are physiological substrates in cells","No identification of partner assembly factors in vivo"]},{"year":1997,"claim":"Addressed where NAP1L4 acts by showing it shuttles between cytoplasm and nucleus, supporting a histone-delivery role.","evidence":"Subcellular fractionation/imaging of recombinant protein","pmids":["9325046"],"confidence":"Medium","gaps":["Shuttling signals/receptors not identified","Functional coupling of shuttling to histone delivery inferred, not demonstrated","No regulation of localization characterized"]},{"year":2019,"claim":"Linked NAP1L4 to cell fate control by showing it modulates p53 acetylation in a residue-specific manner, biasing cells toward arrest versus apoptosis.","evidence":"siRNA knockdown with western blots for K320/K382 acetylation and p21/Bax readouts in mammalian cells","pmids":["31634504"],"confidence":"Medium","gaps":["Mechanism of how a histone chaperone alters site-specific p53 acetylation unknown","Direct interaction with p53 or acetyltransferases/deacetylases not shown","Single knockdown method without rescue"]},{"year":2020,"claim":"Identified NAP1L4 as a restriction factor against PCV2, binding capsid protein and dampening a cGAS-driven IFN-β response that the virus exploits.","evidence":"Co-IP domain mapping, CRISPR/Cas9 knockout and overexpression in PK15 cells, viral titer and IFN-β readouts","pmids":["32605741"],"confidence":"Medium","gaps":["Mechanistic link from NAP1L4 to CCP5/CCP6 expression unresolved","Whether capsid binding or chaperone activity drives restriction unclear","Single lab/system"]},{"year":2021,"claim":"Showed NAP1L4 is a proviral host factor for CHIKV, binding the phospho-nsP3 hypervariable domain in a CK2-dependent manner to stimulate replication.","evidence":"Co-IP and binding assays with CK2 inhibition/mutation and viral replication assays","pmids":["34076483"],"confidence":"Medium","gaps":["Functional role of the bound NAP1L4 in the replication complex undefined","Whether chaperone activity is required for the proviral effect unknown","No structural detail of the HVD-binding motifs"]},{"year":2024,"claim":"Reported NAP1L4 as a prenylated protein whose lipidation governs cardiomyocyte mitosis and centrosome homeostasis, implying a non-chromatin role in cell division.","evidence":"Prenyl probe labeling/MS and chemical/genetic prenylation perturbation in hPSC-derived cardiomyocytes (preprint)","pmids":["bio_10.1101_2024.07.01.601625"],"confidence":"Low","gaps":["Preprint, not peer reviewed; prenylation site not defined","Mechanistic connection between prenylation and centrosome/mitosis control unknown","Relationship to histone chaperone function unestablished"]},{"year":null,"claim":"How NAP1L4's chromatin chaperone activity mechanistically intersects with its p53 regulation, viral interactions, and prenylation-dependent mitotic roles remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying mechanism connecting histone chaperone activity to p53 and centrosome functions","No structural data on any complex","Physiological substrate and partner landscape in cells unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["TP53","NSP3","CAP","NAP1L1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99733","full_name":"Nucleosome assembly protein 1-like 4","aliases":["Histone chaperone NAP1L4","Nucleosome assembly protein 2","NAP-2"],"length_aa":375,"mass_kda":42.8,"function":"Acts as a histone chaperone in nucleosome assembly","subcellular_location":"Nucleus; Chromosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q99733/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NAP1L4","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":"H1F0","stoichiometry":10.0},{"gene":"ARL3","stoichiometry":4.0},{"gene":"HIST2H2BE","stoichiometry":4.0},{"gene":"IPO5","stoichiometry":4.0},{"gene":"IPO7","stoichiometry":4.0},{"gene":"RBM39","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CEP78","stoichiometry":0.2},{"gene":"MYO9B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NAP1L4","total_profiled":1310},"omim":[{"mim_id":"602820","title":"HISTONE GENE CLUSTER 3, H3 HISTONE; HIST3H3","url":"https://www.omim.org/entry/602820"},{"mim_id":"601651","title":"NUCLEOSOME ASSEMBLY PROTEIN 1-LIKE 4; NAP1L4","url":"https://www.omim.org/entry/601651"},{"mim_id":"164060","title":"NUCLEOSOME ASSEMBLY PROTEIN 1-LIKE 1; NAP1L1","url":"https://www.omim.org/entry/164060"},{"mim_id":"130650","title":"BECKWITH-WIEDEMANN SYNDROME; BWS","url":"https://www.omim.org/entry/130650"}],"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/NAP1L4"},"hgnc":{"alias_symbol":["NAP2"],"prev_symbol":[]},"alphafold":{"accession":"Q99733","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99733","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99733-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99733-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NAP1L4","jax_strain_url":"https://www.jax.org/strain/search?query=NAP1L4"},"sequence":{"accession":"Q99733","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99733.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99733/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99733"}},"corpus_meta":[{"pmid":"9325046","id":"PMC_9325046","title":"Functional characterization of human nucleosome assembly protein-2 (NAP1L4) suggests a role as a histone chaperone.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9325046","citation_count":93,"is_preprint":false},{"pmid":"32451710","id":"PMC_32451710","title":"A novel NAP1L4/NUTM1 fusion arising from translocation t(11;15)(p15;q12) in a myeloid neoplasm with eosinophilia and rearrangement of PDGFRA highlights an unusual clinical feature and therapeutic reaction.","date":"2020","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/32451710","citation_count":22,"is_preprint":false},{"pmid":"34076483","id":"PMC_34076483","title":"NAP1L1 and NAP1L4 Binding to Hypervariable Domain of Chikungunya Virus nsP3 Protein Is Bivalent and Requires Phosphorylation.","date":"2021","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/34076483","citation_count":19,"is_preprint":false},{"pmid":"31634504","id":"PMC_31634504","title":"Nucleosome assembly proteins NAP1L1 and NAP1L4 modulate p53 acetylation to regulate cell fate.","date":"2019","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31634504","citation_count":17,"is_preprint":false},{"pmid":"20644730","id":"PMC_20644730","title":"Telomeric NAP1L4 and OSBPL5 of the KCNQ1 cluster, and the DECORIN gene are not imprinted in human trophoblast stem cells.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20644730","citation_count":11,"is_preprint":false},{"pmid":"39102213","id":"PMC_39102213","title":"CircNAP1L4 regulates pulmonary artery smooth muscle cell proliferation via the NAP1L4-mediated super-enhancer-driven glycolysis gene hexokinase II (HK II) in pulmonary hypertension.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/39102213","citation_count":9,"is_preprint":false},{"pmid":"27440996","id":"PMC_27440996","title":"Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent.","date":"2016","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/27440996","citation_count":9,"is_preprint":false},{"pmid":"22500112","id":"PMC_22500112","title":"Characterization, tissue expression, and imprinting analysis of the porcine CDKN1C and NAP1L4 genes.","date":"2012","source":"Journal of biomedicine & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/22500112","citation_count":8,"is_preprint":false},{"pmid":"32605741","id":"PMC_32605741","title":"NAP1L4 inhibits porcine circovirus type 2 replication via IFN-β signaling pathway.","date":"2020","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32605741","citation_count":7,"is_preprint":false},{"pmid":"26440077","id":"PMC_26440077","title":"Biallelic expression of Tssc4, Nap1l4, Phlda2 and Osbpl5 in adult cattle.","date":"2015","source":"Journal of genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26440077","citation_count":6,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.01.601625","title":"Prenylation controls proliferation in human pluripotent stem cell-derived cardiomyocytes","date":"2024-07-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.01.601625","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8300,"output_tokens":1677,"usd":0.025028,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8453,"output_tokens":2325,"usd":0.050195,"stage2_stop_reason":"end_turn"},"total_usd":0.075223,"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\": 1997,\n      \"finding\": \"Recombinant NAP1L4 (NAP-2) protein interacts with both core and linker histones and can transfer histones onto naked DNA templates in vitro, demonstrating histone chaperone activity. Deletion mutagenesis showed that both NH2- and COOH-terminal domains are required for this histone transfer activity.\",\n      \"method\": \"In vitro histone binding and transfer assays with recombinant protein purified from E. coli; deletion mutagenesis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of histone transfer activity combined with deletion mutagenesis defining functional domains, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9325046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"NAP1L4 (NAP-2) shuttles between the cytoplasm and the nucleus, consistent with a role as a histone chaperone delivering histones to the nucleus.\",\n      \"method\": \"Subcellular localization studies (fractionation/imaging of recombinant NAP-2)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment in single lab; functional link inferred but consistent with in vitro chaperone data\",\n      \"pmids\": [\"9325046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NAP1L4 knockdown increases Lys320 acetylation of p53 and enhances expression of the pro-arrest gene p21, thereby suppressing cell growth under normal conditions. Under genotoxic stress, NAP1L4 knockdown decreases Lys382 acetylation of p53 and attenuates proapoptotic Bax levels, suppressing apoptosis. These results indicate NAP1L4 modulates cell fate by controlling site-specific p53 acetylation.\",\n      \"method\": \"siRNA knockdown of NAP1L4 in mammalian cells, western blot for p53 acetylation at specific lysines (K320, K382), and measurement of p21 and Bax expression levels\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean knockdown with defined molecular readouts (site-specific p53 acetylation), single lab, single method type\",\n      \"pmids\": [\"31634504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NAP1L4 (and NAP1L1) binds to the hypervariable domain (HVD) of Chikungunya virus nsP3 at two motifs located upstream and downstream of the G3BP-binding motifs. This interaction requires CK2 kinase-mediated phosphorylation of the HVD and has a strong stimulatory effect on CHIKV replication in vertebrate cells.\",\n      \"method\": \"Co-immunoprecipitation, binding assays, phosphorylation-dependency experiments with CK2 kinase inhibition/mutation, viral replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays with phosphorylation requirement defined, functional viral replication readout, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"34076483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NAP1L4 directly interacts with porcine circovirus type 2 (PCV2) capsid protein (Cap) via NAP1L4 residues 124–279. Overexpression of NAP1L4 inhibits PCV2 Cap and Rep expression and reduces viral DNA copies and titers, while CRISPR/Cas9 knockout of NAP1L4 increases viral replication. Mechanistically, NAP1L4 depletion facilitates CCP5 and CCP6 expression, which activates cGAS to promote IFN-β production, and IFN-β stimulation promotes PCV2 replication.\",\n      \"method\": \"Co-IP to map interaction domain; NAP1L4 overexpression and CRISPR/Cas9 knockout in PK15 cells; qRT-PCR and western blot for viral and IFN-β markers; viral titer measurement\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by deletion, genetic KO and OE with defined molecular pathway (cGAS-IFN-β), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32605741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAP1L4 is a prenylated protein in human cardiac cells. Prenylation of NAP1L4 regulates cardiomyocyte mitosis and centrosome homeostasis, as shown by chemical and genetic perturbation of the mevalonate/prenylation pathway in human pluripotent stem cell-derived cardiomyocytes.\",\n      \"method\": \"Prenyl probe labeling and mass spectrometry identification; chemical inhibition and genetic perturbation of prenylation; cardiomyocyte proliferation and centrosome assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, prenylation identified by chemical probe/MS with functional readout but limited mechanistic detail in abstract\",\n      \"pmids\": [\"bio_10.1101_2024.07.01.601625\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NAP1L4 is a histone chaperone that binds core and linker histones and transfers them onto DNA via both its N- and C-terminal domains, shuttling between cytoplasm and nucleus; it also modulates p53 acetylation at specific lysines (K320, K382) to regulate cell fate decisions, interacts with viral proteins (CHIKV nsP3 HVD in a phosphorylation-dependent manner, and PCV2 Cap) to influence viral replication, and undergoes prenylation that controls cardiomyocyte mitosis and centrosome homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NAP1L4 is a histone chaperone that binds both core and linker histones and transfers them onto naked DNA, an activity requiring both its N- and C-terminal domains [#0], and it shuttles between cytoplasm and nucleus consistent with delivering histones into the nucleus [#1]. Beyond chromatin assembly, NAP1L4 regulates cell fate by controlling site-specific p53 acetylation: its loss raises Lys320 acetylation and the pro-arrest target p21 under normal conditions while lowering Lys382 acetylation and the proapoptotic factor Bax under genotoxic stress [#2]. NAP1L4 is also exploited or countered by viruses — it binds the phosphorylated hypervariable domain of Chikungunya virus nsP3 (a CK2-dependent interaction) to stimulate viral replication [#3], and it directly binds the porcine circovirus 2 capsid protein through residues 124–279, restricting replication by suppressing a CCP5/CCP6–cGAS–IFN-β axis [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established NAP1L4 as a bona fide histone chaperone by showing it both binds histones and deposits them onto DNA, and mapped this activity to two terminal domains.\",\n      \"evidence\": \"In vitro histone binding and transfer assays with recombinant protein plus deletion mutagenesis\",\n      \"pmids\": [\"9325046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the histone-binding interface\",\n        \"In vitro deposition does not establish which histones are physiological substrates in cells\",\n        \"No identification of partner assembly factors in vivo\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Addressed where NAP1L4 acts by showing it shuttles between cytoplasm and nucleus, supporting a histone-delivery role.\",\n      \"evidence\": \"Subcellular fractionation/imaging of recombinant protein\",\n      \"pmids\": [\"9325046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Shuttling signals/receptors not identified\",\n        \"Functional coupling of shuttling to histone delivery inferred, not demonstrated\",\n        \"No regulation of localization characterized\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked NAP1L4 to cell fate control by showing it modulates p53 acetylation in a residue-specific manner, biasing cells toward arrest versus apoptosis.\",\n      \"evidence\": \"siRNA knockdown with western blots for K320/K382 acetylation and p21/Bax readouts in mammalian cells\",\n      \"pmids\": [\"31634504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of how a histone chaperone alters site-specific p53 acetylation unknown\",\n        \"Direct interaction with p53 or acetyltransferases/deacetylases not shown\",\n        \"Single knockdown method without rescue\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified NAP1L4 as a restriction factor against PCV2, binding capsid protein and dampening a cGAS-driven IFN-β response that the virus exploits.\",\n      \"evidence\": \"Co-IP domain mapping, CRISPR/Cas9 knockout and overexpression in PK15 cells, viral titer and IFN-β readouts\",\n      \"pmids\": [\"32605741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link from NAP1L4 to CCP5/CCP6 expression unresolved\",\n        \"Whether capsid binding or chaperone activity drives restriction unclear\",\n        \"Single lab/system\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed NAP1L4 is a proviral host factor for CHIKV, binding the phospho-nsP3 hypervariable domain in a CK2-dependent manner to stimulate replication.\",\n      \"evidence\": \"Co-IP and binding assays with CK2 inhibition/mutation and viral replication assays\",\n      \"pmids\": [\"34076483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of the bound NAP1L4 in the replication complex undefined\",\n        \"Whether chaperone activity is required for the proviral effect unknown\",\n        \"No structural detail of the HVD-binding motifs\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reported NAP1L4 as a prenylated protein whose lipidation governs cardiomyocyte mitosis and centrosome homeostasis, implying a non-chromatin role in cell division.\",\n      \"evidence\": \"Prenyl probe labeling/MS and chemical/genetic prenylation perturbation in hPSC-derived cardiomyocytes (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.01.601625\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Preprint, not peer reviewed; prenylation site not defined\",\n        \"Mechanistic connection between prenylation and centrosome/mitosis control unknown\",\n        \"Relationship to histone chaperone function unestablished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NAP1L4's chromatin chaperone activity mechanistically intersects with its p53 regulation, viral interactions, and prenylation-dependent mitotic roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unifying mechanism connecting histone chaperone activity to p53 and centrosome functions\",\n        \"No structural data on any complex\",\n        \"Physiological substrate and partner landscape in cells unmapped\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TP53\",\n      \"nsP3\",\n      \"Cap\",\n      \"NAP1L1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}