{"gene":"HIVEP1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1989,"finding":"HIVEP1 (HIV-EP1) was identified as a zinc finger protein that specifically binds to the HIV-1 enhancer (NF-κB binding site, GGGACTTTCC). DNase I footprinting with recombinant protein expressed in E. coli demonstrated direct, specific binding to the HIV-1 enhancer sequence. The protein contains two tandem C2H2-type zinc finger sequences required for DNA binding.","method":"Southwestern cloning, DNase I footprinting with recombinant protein expressed in E. coli","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro DNA-binding assay with recombinant protein and footprinting; foundational biochemical characterization replicated by subsequent studies","pmids":["2504707"],"is_preprint":false},{"year":1991,"finding":"HIVEP1 (HIV-EP1/MBP-1/PRDII-BF1) encodes a ~298-kDa protein with two widely separated zinc finger DNA-binding domains, each of which binds the same κB DNA sequence. The gene was mapped to human chromosome 6p22.3-p24.","method":"cDNA analysis, chromosomal mapping by in situ hybridization and somatic cell hybrid analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromosomal localization and structural characterization by molecular cloning and mapping; single lab","pmids":["2037300"],"is_preprint":false},{"year":1992,"finding":"HIVEP1 (PRDII-BF1) produces two protein isoforms via alternative splicing, both of which specifically bind to the HIV NF-κB motif and related enhancer elements in the immunoglobulin κ, class I MHC, and IL-2 receptor genes. When fused to the GAL4 DNA-binding domain, PRDII-BF1-derived proteins did not stimulate basal or Tat-induced HIV gene expression, indicating HIVEP1 does not act as a transcriptional activator of HIV LTR in this context.","method":"DNA-binding assays, GAL4 fusion cotransfection with HIV LTR-CAT reporter","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay with GAL4-fusion constructs; single lab with two orthogonal methods (binding + transcription assay)","pmids":["1727488"],"is_preprint":false},{"year":1990,"finding":"The α A-CRYBP1 regulatory site (to which HIVEP1/αA-CRYBP1 binds) in the mouse αA-crystallin promoter activated transcription in a mouse lens epithelial cell line in a copy-number- and cell-type-dependent manner; a single copy conferred lens specificity while multiple copies extended expression to non-lens cells including fibroblasts and B cells.","method":"Transient transfection of thymidine kinase reporter constructs in lens and non-lens cell lines","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay with defined regulatory element; single lab","pmids":["2247086"],"is_preprint":false},{"year":1993,"finding":"Multiple HIVEP1 (αA-CRYBP1) antigenically related proteins of different sizes (50 kDa, 90 kDa, and >200 kDa) interact with the αA-CRYBP1 regulatory sequence, as shown by UV-crosslinking and double-label immunoblotting with a specific antibody. The large isoform (>200 kDa) was detected only in fibroblasts, not in lens cells, suggesting differential processing or alternative splicing generates tissue-specific forms.","method":"UV-crosslinking of protein-DNA complexes, double-label immunoblotting with specific antibody against αA-CRYBP1","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-DNA crosslinking with antibody confirmation; single lab, two orthogonal methods","pmids":["8406008"],"is_preprint":false},{"year":1993,"finding":"The DE-1 and αA-CRYBP1 binding sites in the mouse αA-crystallin promoter are functionally redundant for lens-specific expression in transgenic mice; individual site mutations preserved lens activity, but simultaneous mutation or deletion of both sites abolished lens expression entirely.","method":"Site-directed mutagenesis, stable transformation of lens cells, transgenic mouse CAT reporter assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo transgenic mouse epistasis combined with stable cell transfection and mutagenesis; multiple orthogonal approaches in one study","pmids":["8332460"],"is_preprint":false},{"year":1995,"finding":"Novel zinc-chelating heterocyclic compounds inhibit the DNA-binding activity of HIVEP1 (HIV-EP1) by removing zinc from its C2H2 zinc finger domain, demonstrating that zinc coordination is essential for HIVEP1 DNA-binding activity. Distinct compounds selectively inhibited either HIVEP1 or NF-κB DNA binding without affecting the other, enabling functional discrimination between the two κB-site-binding proteins.","method":"In vitro DNA-binding inhibition assay, NMR confirmation of zinc chelation","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay with NMR structural confirmation; single lab","pmids":["7650680"],"is_preprint":false},{"year":1996,"finding":"Novel pyridine-aminoalkanethiol zinc chelators inhibit HIVEP1 DNA-binding with IC50 ~4 µM (10-fold more potent than histidine-based inhibitors), and do so by a mechanism distinct from histidine-based chelators, further confirming that zinc coordination in the zinc finger domain is the critical determinant of HIVEP1 DNA-binding activity.","method":"In vitro DNA-binding inhibition assay with purified HIVEP1 protein","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay with defined IC50; single lab, extends prior finding","pmids":["8558519"],"is_preprint":false},{"year":2009,"finding":"HIVEP1 (via its C-terminal fragment Cirip/CIRIP, which retains the zinc fingers) physically interacts with Cirhin (CIRH1A) in the nuclei of HeLa cells. This interaction upregulates transcription through a canonical NF-κB element. The NAIC-associated R565W mutation in Cirhin weakens this interaction and reduces transactivation of the NF-κB element, establishing a functional Cirhin–HIVEP1 complex in transcriptional regulation.","method":"Yeast two-hybrid screening, co-immunoprecipitation from nuclear extracts, mammalian cell NF-κB reporter assay","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP confirming yeast two-hybrid interaction, plus functional reporter assay; multiple orthogonal methods in one study","pmids":["19732766"],"is_preprint":false},{"year":2021,"finding":"HIVEP1 functions as a negative regulator of NF-κB in monocytes/macrophages. In complementary overexpression and gene-deletion experiments, HIVEP1 inhibited NF-κB activity and induction of NF-κB-responsive genes. HIVEP1 was shown to bind promoter regions of NF-κB-responsive genes by ChIP. In LPS-stimulated murine Hivep1-knockout macrophages and HIVEP1-knockdown zebrafish infected with Streptococcus pneumoniae, cytokine production was increased, demonstrating HIVEP1 suppresses proinflammatory responses to bacterial stimuli in vitro and in vivo.","method":"Overexpression and gene deletion experiments, RNA sequencing, transcription factor binding site analysis, ChIP (promoter binding), murine Hivep1 KO macrophages, HIVEP1-knockdown zebrafish infection model","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, OE, ChIP, in vivo zebrafish model) across independent systems establishing HIVEP1 as negative regulator of NF-κB","pmids":["34804025"],"is_preprint":false},{"year":2025,"finding":"HIVEP1 acts as a transcription factor that promotes TH17 cell differentiation and cytokine production by transcriptionally activating ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme of polyamine metabolism. Specific knockout of Hivep1 in IL-17A+ and CD4+ T cells in mice impaired TH17 differentiation and alleviated NASH development, and pharmacological inhibition of ODC1 phenocopied the protective effect.","method":"scATAC-seq, scRNA-seq, conditional Hivep1 knockout in IL-17A+ and CD4+ T cells, transcriptional target identification (ODC1), pharmacological ODC1 inhibition in vivo","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model with defined phenotype, transcriptomic data, and pharmacological validation of identified downstream target; multiple orthogonal methods","pmids":["41124285"],"is_preprint":false}],"current_model":"HIVEP1 is a large C2H2-type zinc finger transcription factor that binds κB DNA motifs (HIV-1 LTR enhancer, immunoglobulin κ, MHC class I, β-interferon, and αA-crystallin promoter sequences) through zinc-dependent DNA-binding domains; it forms a nuclear complex with Cirhin to upregulate NF-κB-responsive transcription, yet acts as a negative regulator of NF-κB in innate immune cells (monocytes/macrophages) by binding promoters of NF-κB target genes and suppressing cytokine production; and in TH17 cells it drives proinflammatory differentiation by transcriptionally activating ODC1 to reprogram polyamine metabolism."},"narrative":{"mechanistic_narrative":"HIVEP1 is a large C2H2-type zinc finger transcription factor that recognizes κB DNA motifs across diverse regulatory elements, including the HIV-1 LTR enhancer and the immunoglobulin κ, MHC class I, and IL-2 receptor enhancers [PMID:2504707, PMID:1727488]. It contains two widely separated tandem zinc finger domains, each independently competent to bind the same κB sequence, and its DNA binding is strictly zinc-dependent — removal of zinc from the finger domains abolishes binding [PMID:2037300, PMID:7650680]. HIVEP1 also binds the αA-CRYBP1 site in the αA-crystallin promoter, where together with a redundant DE-1 element it is required for lens-specific transcription in vivo [PMID:8332460]. Functionally, HIVEP1 is context-dependent: through its C-terminal zinc-finger-containing fragment it forms a nuclear complex with Cirhin (CIRH1A) that transactivates an NF-κB element, an interaction disrupted by the NAIC-associated Cirhin R565W mutation [PMID:19732766], yet in monocytes/macrophages it acts as a negative regulator of NF-κB, binding promoters of NF-κB-responsive genes and suppressing proinflammatory cytokine output during bacterial challenge [PMID:34804025]. In TH17 cells it drives proinflammatory differentiation by transcriptionally activating ODC1, the rate-limiting enzyme of polyamine metabolism, linking HIVEP1 to NASH pathology [PMID:41124285].","teleology":[{"year":1989,"claim":"Established HIVEP1 as a sequence-specific DNA-binding protein for the HIV-1 enhancer κB site, defining its founding biochemical activity.","evidence":"Southwestern cloning and DNase I footprinting with recombinant protein from E. coli","pmids":["2504707"],"confidence":"High","gaps":["No cellular function or transcriptional output assayed","Affinity/specificity relative to other κB-binding factors not quantified"]},{"year":1991,"claim":"Resolved the protein architecture, showing two widely separated zinc finger domains each binding the same κB motif, and mapped the gene to 6p22.3-p24.","evidence":"cDNA analysis and chromosomal mapping by in situ hybridization and somatic cell hybrids","pmids":["2037300"],"confidence":"Medium","gaps":["Functional role of dual independent binding domains unresolved","No in vivo target genes defined"]},{"year":1990,"claim":"Demonstrated the αA-CRYBP1/HIVEP1 binding site is a functional, cell-type- and copy-number-dependent transcriptional element in lens promoters, extending HIVEP1's targets beyond immune enhancers.","evidence":"Transient transfection of TK reporter constructs in lens and non-lens cell lines","pmids":["2247086"],"confidence":"Medium","gaps":["Direct HIVEP1 occupancy at endogenous promoter not shown","Activator versus repressor role not distinguished"]},{"year":1992,"claim":"Showed HIVEP1 produces multiple κB-binding isoforms by alternative splicing but does not activate the HIV LTR in a GAL4-fusion context, indicating it is not a straightforward LTR transactivator.","evidence":"DNA-binding assays and GAL4-fusion cotransfection with HIV LTR-CAT reporter","pmids":["1727488"],"confidence":"Medium","gaps":["Native promoter context may differ from GAL4-fusion readout","Isoform-specific functions not separated"]},{"year":1993,"claim":"Identified tissue-specific HIVEP1 protein forms (50, 90, >200 kDa) bound to the αA-CRYBP1 site and established functional redundancy of the αA-CRYBP1 and DE-1 sites for lens expression in transgenic mice.","evidence":"UV-crosslinking, double-label immunoblotting; site-directed mutagenesis and transgenic mouse CAT reporter assays","pmids":["8406008","8332460"],"confidence":"High","gaps":["Origin of size variants (processing vs splicing) unresolved","Which isoform mediates lens activity unknown"]},{"year":1995,"claim":"Demonstrated zinc coordination is essential for HIVEP1 DNA binding and that selective zinc chelators can discriminate HIVEP1 from NF-κB, providing a tool to dissect the two κB-site factors.","evidence":"In vitro DNA-binding inhibition assays with NMR confirmation of zinc chelation","pmids":["7650680"],"confidence":"Medium","gaps":["Cellular efficacy of chelators not established","No structural model of the finger-DNA complex"]},{"year":1996,"claim":"Confirmed and refined the zinc-dependence mechanism with more potent pyridine-aminoalkanethiol chelators acting by a distinct mechanism.","evidence":"In vitro DNA-binding inhibition assays with purified HIVEP1 (IC50 ~4 µM)","pmids":["8558519"],"confidence":"Medium","gaps":["In vivo activity untested","Selectivity across zinc-finger proteins beyond NF-κB not assessed"]},{"year":2009,"claim":"Identified a direct nuclear protein partner, Cirhin, and showed the HIVEP1 C-terminal fragment–Cirhin complex transactivates an NF-κB element, with a disease-associated Cirhin mutation weakening both interaction and transactivation.","evidence":"Yeast two-hybrid, reciprocal Co-IP from nuclear extracts, and NF-κB reporter assay in HeLa cells","pmids":["19732766"],"confidence":"High","gaps":["Endogenous target genes of the complex not defined","Physiological cell type for the interaction unclear"]},{"year":2021,"claim":"Reframed HIVEP1 as a negative regulator of NF-κB in innate immune cells, binding NF-κB target promoters and suppressing cytokine production in vitro and in vivo.","evidence":"Overexpression, KO, RNA-seq, ChIP in macrophages, and HIVEP1-knockdown zebrafish infection model","pmids":["34804025"],"confidence":"High","gaps":["Mechanism reconciling activation (with Cirhin) versus repression in macrophages unresolved","Direct repressive cofactors not identified"]},{"year":2025,"claim":"Established a metabolic-immune axis in which HIVEP1 drives TH17 differentiation by transcriptionally activating ODC1, contributing to NASH.","evidence":"scATAC-seq, scRNA-seq, conditional Hivep1 KO in T cells, target identification, and pharmacological ODC1 inhibition in vivo","pmids":["41124285"],"confidence":"High","gaps":["Direct HIVEP1 binding at the ODC1 locus versus indirect activation not fully delineated","Relationship to its NF-κB regulatory functions in T cells unknown"]},{"year":null,"claim":"How HIVEP1 switches between activating (Cirhin-associated, ODC1) and repressive (macrophage NF-κB) transcriptional outputs across cell types remains unresolved.","evidence":"No single study reconciles the context-dependent activator/repressor roles","pmids":[],"confidence":"Medium","gaps":["No structural basis for context-dependent cofactor selection","Genome-wide direct target sets across cell types not integrated","Post-translational regulation of activity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,2,4,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,9,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,5,8,9,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,10]}],"complexes":["HIVEP1–Cirhin nuclear complex"],"partners":["CIRH1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15822","full_name":"Zinc finger protein 40","aliases":["Cirhin interaction protein","CIRIP","Gate keeper of apoptosis-activating protein","GAAP","Human immunodeficiency virus type I enhancer-binding protein 1","HIV-EP1","Major histocompatibility complex-binding protein 1","MBP-1","Positive regulatory domain II-binding factor 1","PRDII-BF1"],"length_aa":2718,"mass_kda":296.8,"function":"This protein specifically binds to the DNA sequence 5'-GGGACTTTCC-3' which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV-1. In addition, related sequences are found in the enhancer elements of a number of cellular promoters, including those of the class I MHC, interleukin-2 receptor, and interferon-beta genes. It may act in T-cell activation. Involved in activating HIV-1 gene expression. Isoform 2 and isoform 3 also bind to the IPCS (IRF1 and p53 common sequence) DNA sequence in the promoter region of interferon regulatory factor 1 and p53 genes and are involved in transcription regulation of these genes. Isoform 2 does not activate HIV-1 gene expression. Isoform 2 and isoform 3 may be involved in apoptosis","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P15822/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HIVEP1","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":[],"url":"https://opencell.sf.czbiohub.org/search/HIVEP1","total_profiled":1310},"omim":[{"mim_id":"616698","title":"ZINC FINGER PROTEIN 593; ZNF593","url":"https://www.omim.org/entry/616698"},{"mim_id":"606649","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 ENHANCER-BINDING PROTEIN 3; HIVEP3","url":"https://www.omim.org/entry/606649"},{"mim_id":"194540","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 ENHANCER-BINDING PROTEIN 1; HIVEP1","url":"https://www.omim.org/entry/194540"},{"mim_id":"188050","title":"THROMBOPHILIA DUE TO THROMBIN DEFECT; THPH1","url":"https://www.omim.org/entry/188050"},{"mim_id":"143054","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 ENHANCER-BINDING PROTEIN 2; HIVEP2","url":"https://www.omim.org/entry/143054"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Mitochondria","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HIVEP1"},"hgnc":{"alias_symbol":["CIRIP","MBP-1","CRYBP1","PRDII-BF1","ZAS1","Schnurri-1","ZNF40A"],"prev_symbol":["ZNF40"]},"alphafold":{"accession":"P15822","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15822","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15822-3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15822-3-F1-predicted_aligned_error_v6.png","plddt_mean":47.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HIVEP1","jax_strain_url":"https://www.jax.org/strain/search?query=HIVEP1"},"sequence":{"accession":"P15822","fasta_url":"https://rest.uniprot.org/uniprotkb/P15822.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15822/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15822"}},"corpus_meta":[{"pmid":"7774018","id":"PMC_7774018","title":"Schnurri is required for Drosophila Dpp signaling and encodes a zinc finger protein similar to the mammalian transcription factor PRDII-BF1.","date":"1995","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7774018","citation_count":178,"is_preprint":false},{"pmid":"2504707","id":"PMC_2504707","title":"Putative metal finger structure of the human immunodeficiency virus type 1 enhancer binding protein HIV-EP1.","date":"1989","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2504707","citation_count":80,"is_preprint":false},{"pmid":"25809188","id":"PMC_25809188","title":"Biochemical characterization of a D-psicose 3-epimerase from Treponema primitia ZAS-1 and its application on enzymatic production of D-psicose.","date":"2015","source":"Journal of the science of food and agriculture","url":"https://pubmed.ncbi.nlm.nih.gov/25809188","citation_count":57,"is_preprint":false},{"pmid":"2022670","id":"PMC_2022670","title":"HIV-EP2, a new member of the gene family encoding the human immunodeficiency virus type 1 enhancer-binding protein. Comparison with HIV-EP1/PRDII-BF1/MBP-1.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2022670","citation_count":55,"is_preprint":false},{"pmid":"1727488","id":"PMC_1727488","title":"Regulation of human immunodeficiency virus enhancer function by PRDII-BF1 and c-rel gene products.","date":"1992","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/1727488","citation_count":36,"is_preprint":false},{"pmid":"11161801","id":"PMC_11161801","title":"Structure of the human zinc finger protein HIVEP3: molecular cloning, expression, exon-intron structure, and comparison with paralogous genes HIVEP1 and HIVEP2.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11161801","citation_count":30,"is_preprint":false},{"pmid":"2247086","id":"PMC_2247086","title":"Species-specific lens activation of the thymidine kinase promoter by a single copy of the mouse alpha A-CRYBP1 site and loss of tissue specificity by multimerization.","date":"1990","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2247086","citation_count":25,"is_preprint":false},{"pmid":"7650680","id":"PMC_7650680","title":"Novel zinc chelators with dual activity in the inhibition of the kappa B site-binding proteins HIV-EP1 and NF-kappa B.","date":"1995","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7650680","citation_count":25,"is_preprint":false},{"pmid":"8332460","id":"PMC_8332460","title":"Functional redundancy of the DE-1 and alpha A-CRYBP1 regulatory sites of the mouse alpha A-crystallin promoter.","date":"1993","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8332460","citation_count":24,"is_preprint":false},{"pmid":"8558519","id":"PMC_8558519","title":"Metal-chelating inhibitors of a zinc finger protein HIV-EP1. Remarkable potentiation of inhibitory activity by introduction of SH groups.","date":"1996","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8558519","citation_count":23,"is_preprint":false},{"pmid":"35138483","id":"PMC_35138483","title":"Response surface methodological optimization of L-asparaginase production from the medicinal plant endophyte Acinetobacter baumannii ZAS1.","date":"2022","source":"Journal, genetic engineering & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35138483","citation_count":19,"is_preprint":false},{"pmid":"2037300","id":"PMC_2037300","title":"Localization of the zinc finger DNA-binding protein HIV-EP1/MBP-1/PRDII-BF1 to human chromosome 6p22.3-p24.","date":"1991","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/2037300","citation_count":17,"is_preprint":false},{"pmid":"8406008","id":"PMC_8406008","title":"Binding of tissue-specific forms of alpha A-CRYBP1 to their regulatory sequence in the mouse alpha A-crystallin-encoding gene: double-label immunoblotting of UV-crosslinked complexes.","date":"1993","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8406008","citation_count":17,"is_preprint":false},{"pmid":"34804025","id":"PMC_34804025","title":"HIVEP1 Is a Negative Regulator of NF-κB That Inhibits Systemic Inflammation in Sepsis.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34804025","citation_count":12,"is_preprint":false},{"pmid":"19732766","id":"PMC_19732766","title":"Cirhin up-regulates a canonical NF-kappaB element through strong interaction with Cirip/HIVEP1.","date":"2009","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19732766","citation_count":12,"is_preprint":false},{"pmid":"41124285","id":"PMC_41124285","title":"HIVEP1 aggravates NASH by reprogramming polyamine metabolism in TH17 cells.","date":"2025","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41124285","citation_count":5,"is_preprint":false},{"pmid":"29735745","id":"PMC_29735745","title":"Control of mitotic chromosome condensation by the fission yeast transcription factor Zas1.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29735745","citation_count":3,"is_preprint":false},{"pmid":"35693284","id":"PMC_35693284","title":"Novel HIVEP1-ALK fusion in a patient with lung adenocarcinoma demonstrating sensitivity to alectinib: a case report.","date":"2022","source":"Translational lung cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35693284","citation_count":3,"is_preprint":false},{"pmid":"24719322","id":"PMC_24719322","title":"WITHDRAWN: Modulation of TLR3, TLR4 and TLR7 mediated IFN-β, Rantes and TNFα production by HIVEP1.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24719322","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.13.24310153","title":"Proteome-wide Mendelian randomization study implicates inflammaging biomarkers in retinal vasculature, cardiometabolic diseases and longevity","date":"2024-07-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.13.24310153","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10987,"output_tokens":2928,"usd":0.038441,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10456,"output_tokens":3188,"usd":0.06599,"stage2_stop_reason":"end_turn"},"total_usd":0.104431,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"HIVEP1 (HIV-EP1) was identified as a zinc finger protein that specifically binds to the HIV-1 enhancer (NF-κB binding site, GGGACTTTCC). DNase I footprinting with recombinant protein expressed in E. coli demonstrated direct, specific binding to the HIV-1 enhancer sequence. The protein contains two tandem C2H2-type zinc finger sequences required for DNA binding.\",\n      \"method\": \"Southwestern cloning, DNase I footprinting with recombinant protein expressed in E. coli\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro DNA-binding assay with recombinant protein and footprinting; foundational biochemical characterization replicated by subsequent studies\",\n      \"pmids\": [\"2504707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"HIVEP1 (HIV-EP1/MBP-1/PRDII-BF1) encodes a ~298-kDa protein with two widely separated zinc finger DNA-binding domains, each of which binds the same κB DNA sequence. The gene was mapped to human chromosome 6p22.3-p24.\",\n      \"method\": \"cDNA analysis, chromosomal mapping by in situ hybridization and somatic cell hybrid analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromosomal localization and structural characterization by molecular cloning and mapping; single lab\",\n      \"pmids\": [\"2037300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"HIVEP1 (PRDII-BF1) produces two protein isoforms via alternative splicing, both of which specifically bind to the HIV NF-κB motif and related enhancer elements in the immunoglobulin κ, class I MHC, and IL-2 receptor genes. When fused to the GAL4 DNA-binding domain, PRDII-BF1-derived proteins did not stimulate basal or Tat-induced HIV gene expression, indicating HIVEP1 does not act as a transcriptional activator of HIV LTR in this context.\",\n      \"method\": \"DNA-binding assays, GAL4 fusion cotransfection with HIV LTR-CAT reporter\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay with GAL4-fusion constructs; single lab with two orthogonal methods (binding + transcription assay)\",\n      \"pmids\": [\"1727488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The α A-CRYBP1 regulatory site (to which HIVEP1/αA-CRYBP1 binds) in the mouse αA-crystallin promoter activated transcription in a mouse lens epithelial cell line in a copy-number- and cell-type-dependent manner; a single copy conferred lens specificity while multiple copies extended expression to non-lens cells including fibroblasts and B cells.\",\n      \"method\": \"Transient transfection of thymidine kinase reporter constructs in lens and non-lens cell lines\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay with defined regulatory element; single lab\",\n      \"pmids\": [\"2247086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Multiple HIVEP1 (αA-CRYBP1) antigenically related proteins of different sizes (50 kDa, 90 kDa, and >200 kDa) interact with the αA-CRYBP1 regulatory sequence, as shown by UV-crosslinking and double-label immunoblotting with a specific antibody. The large isoform (>200 kDa) was detected only in fibroblasts, not in lens cells, suggesting differential processing or alternative splicing generates tissue-specific forms.\",\n      \"method\": \"UV-crosslinking of protein-DNA complexes, double-label immunoblotting with specific antibody against αA-CRYBP1\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-DNA crosslinking with antibody confirmation; single lab, two orthogonal methods\",\n      \"pmids\": [\"8406008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The DE-1 and αA-CRYBP1 binding sites in the mouse αA-crystallin promoter are functionally redundant for lens-specific expression in transgenic mice; individual site mutations preserved lens activity, but simultaneous mutation or deletion of both sites abolished lens expression entirely.\",\n      \"method\": \"Site-directed mutagenesis, stable transformation of lens cells, transgenic mouse CAT reporter assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo transgenic mouse epistasis combined with stable cell transfection and mutagenesis; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"8332460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Novel zinc-chelating heterocyclic compounds inhibit the DNA-binding activity of HIVEP1 (HIV-EP1) by removing zinc from its C2H2 zinc finger domain, demonstrating that zinc coordination is essential for HIVEP1 DNA-binding activity. Distinct compounds selectively inhibited either HIVEP1 or NF-κB DNA binding without affecting the other, enabling functional discrimination between the two κB-site-binding proteins.\",\n      \"method\": \"In vitro DNA-binding inhibition assay, NMR confirmation of zinc chelation\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay with NMR structural confirmation; single lab\",\n      \"pmids\": [\"7650680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Novel pyridine-aminoalkanethiol zinc chelators inhibit HIVEP1 DNA-binding with IC50 ~4 µM (10-fold more potent than histidine-based inhibitors), and do so by a mechanism distinct from histidine-based chelators, further confirming that zinc coordination in the zinc finger domain is the critical determinant of HIVEP1 DNA-binding activity.\",\n      \"method\": \"In vitro DNA-binding inhibition assay with purified HIVEP1 protein\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay with defined IC50; single lab, extends prior finding\",\n      \"pmids\": [\"8558519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HIVEP1 (via its C-terminal fragment Cirip/CIRIP, which retains the zinc fingers) physically interacts with Cirhin (CIRH1A) in the nuclei of HeLa cells. This interaction upregulates transcription through a canonical NF-κB element. The NAIC-associated R565W mutation in Cirhin weakens this interaction and reduces transactivation of the NF-κB element, establishing a functional Cirhin–HIVEP1 complex in transcriptional regulation.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation from nuclear extracts, mammalian cell NF-κB reporter assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP confirming yeast two-hybrid interaction, plus functional reporter assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"19732766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HIVEP1 functions as a negative regulator of NF-κB in monocytes/macrophages. In complementary overexpression and gene-deletion experiments, HIVEP1 inhibited NF-κB activity and induction of NF-κB-responsive genes. HIVEP1 was shown to bind promoter regions of NF-κB-responsive genes by ChIP. In LPS-stimulated murine Hivep1-knockout macrophages and HIVEP1-knockdown zebrafish infected with Streptococcus pneumoniae, cytokine production was increased, demonstrating HIVEP1 suppresses proinflammatory responses to bacterial stimuli in vitro and in vivo.\",\n      \"method\": \"Overexpression and gene deletion experiments, RNA sequencing, transcription factor binding site analysis, ChIP (promoter binding), murine Hivep1 KO macrophages, HIVEP1-knockdown zebrafish infection model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, OE, ChIP, in vivo zebrafish model) across independent systems establishing HIVEP1 as negative regulator of NF-κB\",\n      \"pmids\": [\"34804025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIVEP1 acts as a transcription factor that promotes TH17 cell differentiation and cytokine production by transcriptionally activating ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme of polyamine metabolism. Specific knockout of Hivep1 in IL-17A+ and CD4+ T cells in mice impaired TH17 differentiation and alleviated NASH development, and pharmacological inhibition of ODC1 phenocopied the protective effect.\",\n      \"method\": \"scATAC-seq, scRNA-seq, conditional Hivep1 knockout in IL-17A+ and CD4+ T cells, transcriptional target identification (ODC1), pharmacological ODC1 inhibition in vivo\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model with defined phenotype, transcriptomic data, and pharmacological validation of identified downstream target; multiple orthogonal methods\",\n      \"pmids\": [\"41124285\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HIVEP1 is a large C2H2-type zinc finger transcription factor that binds κB DNA motifs (HIV-1 LTR enhancer, immunoglobulin κ, MHC class I, β-interferon, and αA-crystallin promoter sequences) through zinc-dependent DNA-binding domains; it forms a nuclear complex with Cirhin to upregulate NF-κB-responsive transcription, yet acts as a negative regulator of NF-κB in innate immune cells (monocytes/macrophages) by binding promoters of NF-κB target genes and suppressing cytokine production; and in TH17 cells it drives proinflammatory differentiation by transcriptionally activating ODC1 to reprogram polyamine metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HIVEP1 is a large C2H2-type zinc finger transcription factor that recognizes κB DNA motifs across diverse regulatory elements, including the HIV-1 LTR enhancer and the immunoglobulin κ, MHC class I, and IL-2 receptor enhancers [#0, #2]. It contains two widely separated tandem zinc finger domains, each independently competent to bind the same κB sequence, and its DNA binding is strictly zinc-dependent — removal of zinc from the finger domains abolishes binding [#1, #6]. HIVEP1 also binds the αA-CRYBP1 site in the αA-crystallin promoter, where together with a redundant DE-1 element it is required for lens-specific transcription in vivo [#5]. Functionally, HIVEP1 is context-dependent: through its C-terminal zinc-finger-containing fragment it forms a nuclear complex with Cirhin (CIRH1A) that transactivates an NF-κB element, an interaction disrupted by the NAIC-associated Cirhin R565W mutation [#8], yet in monocytes/macrophages it acts as a negative regulator of NF-κB, binding promoters of NF-κB-responsive genes and suppressing proinflammatory cytokine output during bacterial challenge [#9]. In TH17 cells it drives proinflammatory differentiation by transcriptionally activating ODC1, the rate-limiting enzyme of polyamine metabolism, linking HIVEP1 to NASH pathology [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established HIVEP1 as a sequence-specific DNA-binding protein for the HIV-1 enhancer κB site, defining its founding biochemical activity.\",\n      \"evidence\": \"Southwestern cloning and DNase I footprinting with recombinant protein from E. coli\",\n      \"pmids\": [\"2504707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cellular function or transcriptional output assayed\", \"Affinity/specificity relative to other κB-binding factors not quantified\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Resolved the protein architecture, showing two widely separated zinc finger domains each binding the same κB motif, and mapped the gene to 6p22.3-p24.\",\n      \"evidence\": \"cDNA analysis and chromosomal mapping by in situ hybridization and somatic cell hybrids\",\n      \"pmids\": [\"2037300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of dual independent binding domains unresolved\", \"No in vivo target genes defined\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Demonstrated the αA-CRYBP1/HIVEP1 binding site is a functional, cell-type- and copy-number-dependent transcriptional element in lens promoters, extending HIVEP1's targets beyond immune enhancers.\",\n      \"evidence\": \"Transient transfection of TK reporter constructs in lens and non-lens cell lines\",\n      \"pmids\": [\"2247086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HIVEP1 occupancy at endogenous promoter not shown\", \"Activator versus repressor role not distinguished\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Showed HIVEP1 produces multiple κB-binding isoforms by alternative splicing but does not activate the HIV LTR in a GAL4-fusion context, indicating it is not a straightforward LTR transactivator.\",\n      \"evidence\": \"DNA-binding assays and GAL4-fusion cotransfection with HIV LTR-CAT reporter\",\n      \"pmids\": [\"1727488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Native promoter context may differ from GAL4-fusion readout\", \"Isoform-specific functions not separated\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Identified tissue-specific HIVEP1 protein forms (50, 90, >200 kDa) bound to the αA-CRYBP1 site and established functional redundancy of the αA-CRYBP1 and DE-1 sites for lens expression in transgenic mice.\",\n      \"evidence\": \"UV-crosslinking, double-label immunoblotting; site-directed mutagenesis and transgenic mouse CAT reporter assays\",\n      \"pmids\": [\"8406008\", \"8332460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Origin of size variants (processing vs splicing) unresolved\", \"Which isoform mediates lens activity unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrated zinc coordination is essential for HIVEP1 DNA binding and that selective zinc chelators can discriminate HIVEP1 from NF-κB, providing a tool to dissect the two κB-site factors.\",\n      \"evidence\": \"In vitro DNA-binding inhibition assays with NMR confirmation of zinc chelation\",\n      \"pmids\": [\"7650680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular efficacy of chelators not established\", \"No structural model of the finger-DNA complex\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Confirmed and refined the zinc-dependence mechanism with more potent pyridine-aminoalkanethiol chelators acting by a distinct mechanism.\",\n      \"evidence\": \"In vitro DNA-binding inhibition assays with purified HIVEP1 (IC50 ~4 µM)\",\n      \"pmids\": [\"8558519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo activity untested\", \"Selectivity across zinc-finger proteins beyond NF-κB not assessed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a direct nuclear protein partner, Cirhin, and showed the HIVEP1 C-terminal fragment–Cirhin complex transactivates an NF-κB element, with a disease-associated Cirhin mutation weakening both interaction and transactivation.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP from nuclear extracts, and NF-κB reporter assay in HeLa cells\",\n      \"pmids\": [\"19732766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous target genes of the complex not defined\", \"Physiological cell type for the interaction unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reframed HIVEP1 as a negative regulator of NF-κB in innate immune cells, binding NF-κB target promoters and suppressing cytokine production in vitro and in vivo.\",\n      \"evidence\": \"Overexpression, KO, RNA-seq, ChIP in macrophages, and HIVEP1-knockdown zebrafish infection model\",\n      \"pmids\": [\"34804025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism reconciling activation (with Cirhin) versus repression in macrophages unresolved\", \"Direct repressive cofactors not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a metabolic-immune axis in which HIVEP1 drives TH17 differentiation by transcriptionally activating ODC1, contributing to NASH.\",\n      \"evidence\": \"scATAC-seq, scRNA-seq, conditional Hivep1 KO in T cells, target identification, and pharmacological ODC1 inhibition in vivo\",\n      \"pmids\": [\"41124285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct HIVEP1 binding at the ODC1 locus versus indirect activation not fully delineated\", \"Relationship to its NF-κB regulatory functions in T cells unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HIVEP1 switches between activating (Cirhin-associated, ODC1) and repressive (macrophage NF-κB) transcriptional outputs across cell types remains unresolved.\",\n      \"evidence\": \"No single study reconciles the context-dependent activator/repressor roles\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for context-dependent cofactor selection\", \"Genome-wide direct target sets across cell types not integrated\", \"Post-translational regulation of activity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 5, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\"HIVEP1–Cirhin nuclear complex\"],\n    \"partners\": [\"CIRH1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}