{"gene":"NFKBIB","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"NFKBIB (identified as TRIP9) was isolated as a thyroid hormone receptor (TR) interacting protein that interacts with the ligand-binding domain of TR beta only in the absence of T3 (thyroid hormone). A LexA fusion of TRIP9, when coexpressed with both TR and RXR, conferred T3-dependent activation to a reporter gene controlled by LexA binding sites, suggesting an indirect T3-response mechanism.","method":"Yeast interaction trap (two-hybrid), LexA fusion reporter assay","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid screen with reporter assay, no biochemical reconstitution or follow-up in mammalian cells for the TRIP9/NFKBIB interaction specifically","pmids":["7776974"],"is_preprint":false},{"year":2003,"finding":"In human amnion, labour is associated with increased expression of IκBβ (NFKBIB) isoforms (IkBb-1 and IkBb-2). IL-1β stimulation causes rapid degradation of IκBα within 2 h but causes a decrease in IkBb-1 without full recovery by 2 h, and has little effect on IkBb-2. IkBb-2 was found in both cytosolic and nuclear protein fractions, and its nuclear localization suggests a role in protecting NF-κB from inactivation by IκBα to maintain NF-κB-mediated gene transcription.","method":"Western blot, subcellular fractionation, quantitative protein analysis","journal":"Molecular human reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, fractionation with functional inference but no direct functional manipulation of NFKBIB","pmids":["12651903"],"is_preprint":false},{"year":2015,"finding":"In murine macrophages and fibroblasts, IκBβ (NFKBIB) is necessary and sufficient for LPS-induced expression of a select subset of pro-inflammatory genes (IL1β, IL6, IL12β). Low-dose NFκB inhibitors specifically attenuate LPS-induced IκBβ degradation and the expression of these target genes. IκBβ overexpressing mice show attenuated LPS-induced signaling and cytokine expression. A cell-permeable peptide containing the cRel nuclear localization sequence attenuated IL6 expression, confirming that IκBβ acts via its NFκB subunit binding partner cRel.","method":"Gain- and loss-of-function experiments (transgenic overexpressing mice, siRNA/genetic KO), pharmacological inhibition, cell-permeable peptide treatment, cytokine measurement","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transgenic mice, KO, pharmacological inhibitor, cell-permeable peptide), gain- and loss-of-function with defined molecular phenotype, single lab but comprehensive","pmids":["25908863"],"is_preprint":false},{"year":2015,"finding":"miR-20a directly targets the 3' UTR of NFKBIB mRNA (confirmed by luciferase 3'UTR reporter and ago-immunoprecipitation), reducing NFKBIB (IκBβ) protein levels, which leads to upregulation of p65 and downstream targets livin and survivin, thereby activating NF-κB signaling and contributing to cisplatin resistance in gastric cancer cells.","method":"3' UTR luciferase reporter assay, ago-immunoprecipitation, miRNA mimic/inhibitor transfection, Western blot, apoptosis assay","journal":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter and ago-IP are orthogonal methods validating direct miR-20a targeting of NFKBIB mRNA; single lab","pmids":["26286834"],"is_preprint":false},{"year":2017,"finding":"miR-4776 directly targets NFKBIB mRNA (confirmed by ago-immunoprecipitation and 3' UTR luciferase assay) in bronchial epithelial cells. Upon influenza A virus (IAV) infection, miR-4776 is upregulated within 1 h, causing decreased NFKBIB expression and consequently increased NF-κB activity. Overexpression of NFKBIB protein in IAV-infected cells led to lower levels of IAV, indicating NFKBIB suppresses viral replication through NF-κB modulation.","method":"Ago-immunoprecipitation, 3' UTR luciferase assay, miRNA mimic transfection, NFKBIB overexpression, viral load measurement","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (ago-IP and 3'UTR luciferase) confirm direct targeting; functional overexpression experiment with defined viral output phenotype; single lab","pmids":["28448456"],"is_preprint":false},{"year":2019,"finding":"Nuclear KIT binds directly to the promoter of NFKBIB by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, driving enhanced NFKBIB protein expression. Downregulation of NFKBIB by siRNA leads to RELA nuclear translocation, which in turn binds the KIT promoter and reduces KIT transcription/expression and GIST cell viability, establishing a nuclear KIT→NFKBIB→RELA→KIT autoregulatory loop in imatinib-resistant gastrointestinal stromal tumors.","method":"ChIP sequencing, ChIP assay, siRNA knockdown, RELA overexpression, promoter-reporter assay, xenograft model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-seq and ChIP assay directly demonstrate nuclear KIT binding to NFKBIB promoter; siRNA and overexpression provide functional validation; xenograft in vivo confirmation; multiple orthogonal methods in single rigorous study","pmids":["31363162"],"is_preprint":false},{"year":2015,"finding":"IKBB (NFKBIB) acts as a tumor suppressor in nasopharyngeal carcinoma (NPC) by inhibiting NF-κB pathway activity. IKBB overexpression suppresses tumor formation, cell migration, and angiogenesis in NPC cells, and downregulates pro-angiogenic factors (Rantes, Upar, IL6, IL8) at the transcriptional level. Functional complementation via microcell-mediated chromosome transfer identified IKBB as a putative TSG, and its suppressive role is likely mediated by crosstalk with the Akt/Gsk3β signaling pathway.","method":"Microcell-mediated chromosome transfer, functional complementation, migration assay, angiogenesis assay, tumor formation assay, gene expression analysis","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation and multiple cellular phenotype assays; crosstalk with Akt/Gsk3β pathway is mechanistically proposed but supported by expression data; single lab","pmids":["26227166"],"is_preprint":false},{"year":2020,"finding":"LINC01578 (a chromatin-bound lncRNA) binds directly to the NFKBIB promoter and recruits EZH2 to the NFKBIB promoter, repressing NFKBIB expression via epigenetic silencing, thereby activating NF-κB signaling and promoting colon cancer metastasis through a positive feedback loop with the NF-κB/YY1 axis.","method":"ChIP assay, RNA pulldown, promoter reporter assay, siRNA/overexpression, in vivo metastasis model","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and RNA pulldown confirm direct LINC01578 binding to NFKBIB promoter and EZH2 recruitment; functional consequence validated in vivo; single lab","pmids":["33040438"],"is_preprint":false},{"year":2023,"finding":"TSPAN1 inhibits NPC metastasis by directly interacting with IKBB (NFKBIB) protein, and this interaction is essential for preventing overactivation of the NF-κB pathway in NPC cells.","method":"Co-immunoprecipitation (protein interaction), in vitro migration/invasion assay, in vivo metastasis assay, NF-κB pathway reporter/expression analysis","journal":"Cancer gene therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP demonstrating TSPAN1-IKBB interaction; mechanistic follow-up is limited to NF-κB pathway expression changes; single lab","pmids":["38135697"],"is_preprint":false},{"year":2021,"finding":"Using the IκB- (Nfkbia+/-Nfkbib-/-Nfkbie-/-) mouse model with elevated NFκB activity, population dynamics modeling combined with scRNA-seq revealed that elevated NFκB signaling (involving NFKBIB loss) drives myeloid bias in hematopoiesis not only through HSC differentiation bias but also through increased expansion of early myeloid-primed progenitors, an effect conserved when wild-type HSPCs are transplanted into IκB- recipients, indicating the bone marrow microenvironment is sufficient to drive this phenotype.","method":"Triple knockout mouse model (Nfkbia+/-Nfkbib-/-Nfkbie-/-), scRNA-seq, differential equation population dynamics modeling, bone marrow transplantation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model with scRNA-seq and transplantation experiments provide mechanistic pathway placement; modeling adds quantitative insight; NFKBIB contribution is inferred from compound knockout context rather than isolated","pmids":["39791596"],"is_preprint":false}],"current_model":"NFKBIB (IκBβ) functions as an inhibitor of NF-κB signaling by sequestering NF-κB in the cytoplasm; it is selectively required for LPS-induced expression of a subset of pro-inflammatory genes (IL1β, IL6, IL12β) acting through the cRel subunit, its nuclear isoform can maintain persistent NF-κB activity, its promoter is a direct target of nuclear KIT (establishing a KIT→NFKBIB→RELA→KIT autoregulatory loop in GISTs), it is directly targeted post-transcriptionally by miR-20a and miR-4776 (modulating NF-κB activity and viral replication/chemoresistance), it is epigenetically silenced by EZH2 recruited via lncRNA LINC01578, and it physically interacts with TSPAN1 to suppress NF-κB-driven metastasis."},"narrative":{"mechanistic_narrative":"NFKBIB (IκBβ) is a cytoplasmic inhibitor of NF-κB signaling that, distinct from a generic NF-κB brake, is selectively required for the LPS-induced expression of a defined subset of pro-inflammatory genes — IL1β, IL6, and IL12β — acting through its NF-κB subunit binding partner cRel rather than through global NF-κB suppression [PMID:25908863]. Its activity is set by regulated degradation: low-dose NF-κB inhibitors specifically attenuate LPS-induced IκBβ degradation and the resulting cytokine output, and IκBβ overexpression dampens LPS-driven signaling in vivo [PMID:25908863]. Across epithelial and tumor contexts NFKBIB behaves as a restraint on NF-κB, and its loss activates the pathway: it suppresses influenza A virus replication via NF-κB modulation [PMID:28448456], acts as a tumor suppressor in nasopharyngeal carcinoma where it limits migration, angiogenesis, and pro-angiogenic gene expression [PMID:26227166], and physically interacts with TSPAN1 to prevent NF-κB overactivation and metastasis [PMID:38135697]. NFKBIB levels are controlled at multiple regulatory layers — direct post-transcriptional targeting by miR-20a and miR-4776, which lowers IκBβ protein and de-represses NF-κB to drive chemoresistance and viral replication [PMID:26286834, PMID:28448456]; transcriptional induction by nuclear KIT binding its promoter to form a KIT→NFKBIB→RELA→KIT autoregulatory loop in imatinib-resistant GISTs [PMID:31363162]; and epigenetic silencing through LINC01578-mediated recruitment of EZH2 to its promoter, activating NF-κB to promote colon cancer metastasis [PMID:33040438]. At the organismal level, compound IκB loss including Nfkbib drives myeloid-biased hematopoiesis via both progenitor expansion and microenvironmental effects [PMID:39791596].","teleology":[{"year":1995,"claim":"Before any inflammatory role was known, NFKBIB was first captured as a thyroid-hormone-receptor-interacting protein, an early but isolated lead on its protein-interaction behavior.","evidence":"Yeast two-hybrid interaction trap with LexA fusion reporter assay, isolating NFKBIB as TRIP9 binding TRβ ligand-binding domain","pmids":["7776974"],"confidence":"Low","gaps":["Single yeast two-hybrid with no biochemical reconstitution in mammalian cells","Relationship of this TR interaction to NF-κB inhibition never established","No follow-up confirming functional relevance"]},{"year":2003,"claim":"The question of whether IκBβ acts only as a cytoplasmic sequestrant was addressed by showing distinct isoform behavior, with a nuclear-localized isoform implicated in sustaining rather than terminating NF-κB transcription.","evidence":"Western blot, subcellular fractionation and quantitative protein analysis of IκBβ isoforms in IL-1β-stimulated human amnion","pmids":["12651903"],"confidence":"Low","gaps":["Nuclear role inferred from localization, not functional manipulation","Isoform-specific functions not dissected genetically","No direct demonstration of NF-κB protection"]},{"year":2015,"claim":"The central mechanistic advance defined IκBβ not as a generic inhibitor but as a selective, cRel-dependent requirement for a specific LPS-induced pro-inflammatory gene module.","evidence":"Transgenic overexpressing mice, genetic KO/siRNA, pharmacological NF-κB inhibition, and a cRel-NLS cell-permeable peptide with cytokine readout in macrophages and fibroblasts","pmids":["25908863"],"confidence":"High","gaps":["Molecular basis of gene-subset selectivity not fully resolved","Structural detail of IκBβ–cRel complex absent","Degradation kinetics under different stimuli not mapped"]},{"year":2015,"claim":"Post-transcriptional control of NFKBIB was established by showing a microRNA directly tunes IκBβ protein to set NF-κB output and chemoresistance.","evidence":"3'UTR luciferase reporter, ago-immunoprecipitation, miRNA mimic/inhibitor, Western blot and apoptosis assays in gastric cancer cells (miR-20a)","pmids":["26286834"],"confidence":"Medium","gaps":["Downstream livin/survivin link correlative","Single lab, single cancer context","In vivo relevance not tested"]},{"year":2015,"claim":"NFKBIB was placed as a tumor suppressor whose restoration suppresses NF-κB-driven migration and angiogenesis, broadening its role beyond inflammation.","evidence":"Microcell-mediated chromosome transfer, functional complementation, migration/angiogenesis/tumor-formation assays and gene expression in nasopharyngeal carcinoma","pmids":["26227166"],"confidence":"Medium","gaps":["Akt/GSK3β crosstalk proposed from expression data, not mechanism","Direct molecular target of suppression unclear","Single lab"]},{"year":2017,"claim":"A second microRNA axis confirmed direct post-transcriptional silencing of NFKBIB and tied it to antiviral defense, with IκBβ restraining viral replication via NF-κB.","evidence":"Ago-immunoprecipitation, 3'UTR luciferase, miRNA mimic, NFKBIB overexpression and viral-load measurement in IAV-infected bronchial epithelial cells (miR-4776)","pmids":["28448456"],"confidence":"Medium","gaps":["Which NF-κB-dependent antiviral effectors mediate restraint unspecified","Single cell system","miR-4776 induction mechanism not defined"]},{"year":2019,"claim":"Transcriptional regulation of NFKBIB was uncovered as part of an autoregulatory circuit, showing nuclear KIT directly induces the NFKBIB promoter to constrain RELA in drug-resistant GIST.","evidence":"ChIP-seq, ChIP assay, siRNA knockdown, RELA overexpression, promoter-reporter and xenograft in imatinib-resistant gastrointestinal stromal tumors","pmids":["31363162"],"confidence":"High","gaps":["Generality of the KIT→NFKBIB→RELA→KIT loop beyond GIST untested","Direct KIT-NFKBIB promoter contact site not mapped at base resolution"]},{"year":2020,"claim":"Epigenetic silencing emerged as a third regulatory layer, with a chromatin-bound lncRNA recruiting EZH2 to repress NFKBIB and unleash NF-κB-driven metastasis.","evidence":"ChIP, RNA pulldown, promoter reporter, siRNA/overexpression and in vivo metastasis model in colon cancer (LINC01578/EZH2)","pmids":["33040438"],"confidence":"Medium","gaps":["Histone mark deposition at NFKBIB promoter not directly profiled","Generalizability beyond colon cancer untested","Single lab"]},{"year":2021,"claim":"Compound IκB genetics placed NFKBIB loss in hematopoietic regulation, showing elevated NF-κB drives myeloid bias through both progenitor expansion and the bone marrow microenvironment.","evidence":"Nfkbia+/-Nfkbib-/-Nfkbie-/- mouse model with scRNA-seq, population dynamics modeling and bone marrow transplantation","pmids":["39791596"],"confidence":"Medium","gaps":["NFKBIB contribution inferred from compound knockout, not isolated","Cell-autonomous vs microenvironmental contributions of NFKBIB specifically not separated"]},{"year":2023,"claim":"A direct protein partner restraining NF-κB was identified, with TSPAN1 binding IκBβ to prevent pathway overactivation and metastasis.","evidence":"Co-immunoprecipitation, migration/invasion assays, in vivo metastasis assay and NF-κB pathway analysis in nasopharyngeal carcinoma","pmids":["38135697"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation or structural mapping","Mechanism of how TSPAN1 binding affects IκBβ activity unresolved","Single lab"]},{"year":null,"claim":"How the multiple regulatory layers (degradation, miRNA, transcriptional, epigenetic, protein interaction) are integrated to set IκBβ levels in a given cell, and the structural basis for its cRel-selective gene control, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of IκBβ–cRel selectivity","No unified model coupling NFKBIB transcriptional and post-transcriptional control","Isoform-specific nuclear function not mechanistically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,4,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","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-168256","term_label":"Immune System","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,7]}],"complexes":[],"partners":["REL","RELA","KIT","TSPAN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15653","full_name":"NF-kappa-B inhibitor beta","aliases":["I-kappa-B-beta","IkB-B","IkB-beta","IkappaBbeta","Thyroid receptor-interacting protein 9","TR-interacting protein 9","TRIP-9"],"length_aa":356,"mass_kda":37.8,"function":"Inhibits NF-kappa-B by complexing with and trapping it in the cytoplasm. However, the unphosphorylated form resynthesized after cell stimulation is able to bind NF-kappa-B allowing its transport to the nucleus and protecting it to further NFKBIA-dependent inactivation. Association with inhibitor kappa B-interacting NKIRAS1 and NKIRAS2 prevent its phosphorylation rendering it more resistant to degradation, explaining its slower degradation","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15653/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NFKBIB","classification":"Not Classified","n_dependent_lines":52,"n_total_lines":1208,"dependency_fraction":0.04304635761589404},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NFKB1","stoichiometry":10.0},{"gene":"RELA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NFKBIB","total_profiled":1310},"omim":[{"mim_id":"610877","title":"PROTEIN PHOSPHATASE 6, REGULATORY SUBUNIT 2; PPP6R2","url":"https://www.omim.org/entry/610877"},{"mim_id":"610875","title":"PROTEIN PHOSPHATASE 6, REGULATORY SUBUNIT 1; PPP6R1","url":"https://www.omim.org/entry/610875"},{"mim_id":"604834","title":"TANK-BINDING KINASE 1; TBK1","url":"https://www.omim.org/entry/604834"},{"mim_id":"604548","title":"NUCLEAR FACTOR KAPPA-B INHIBITOR, EPSILON; NFKBIE","url":"https://www.omim.org/entry/604548"},{"mim_id":"604495","title":"NUCLEAR FACTOR KAPPA-B INHIBITOR, BETA; NFKBIB","url":"https://www.omim.org/entry/604495"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":72.2}],"url":"https://www.proteinatlas.org/search/NFKBIB"},"hgnc":{"alias_symbol":["IKBB","TRIP9"],"prev_symbol":[]},"alphafold":{"accession":"Q15653","domains":[{"cath_id":"1.25.40.20","chopping":"49-150","consensus_level":"medium","plddt":96.5552,"start":49,"end":150}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15653","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15653-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15653-F1-predicted_aligned_error_v6.png","plddt_mean":76.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NFKBIB","jax_strain_url":"https://www.jax.org/strain/search?query=NFKBIB"},"sequence":{"accession":"Q15653","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15653.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15653/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15653"}},"corpus_meta":[{"pmid":"7776974","id":"PMC_7776974","title":"Two 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biases.","date":"2025","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/39791596","citation_count":15,"is_preprint":false},{"pmid":"36290677","id":"PMC_36290677","title":"M6A RNA Methylation Mediates NOD1/NF-kB Signaling Activation in the Liver of Piglets Challenged with Lipopolysaccharide.","date":"2022","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36290677","citation_count":15,"is_preprint":false},{"pmid":"34539638","id":"PMC_34539638","title":"The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34539638","citation_count":14,"is_preprint":false},{"pmid":"34488523","id":"PMC_34488523","title":"Potential biomarkers: differentially expressed proteins of the extrinsic coagulation pathway in plasma samples from patients with 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A LexA fusion of TRIP9, when coexpressed with both TR and RXR, conferred T3-dependent activation to a reporter gene controlled by LexA binding sites, suggesting an indirect T3-response mechanism.\",\n      \"method\": \"Yeast interaction trap (two-hybrid), LexA fusion reporter assay\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid screen with reporter assay, no biochemical reconstitution or follow-up in mammalian cells for the TRIP9/NFKBIB interaction specifically\",\n      \"pmids\": [\"7776974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In human amnion, labour is associated with increased expression of IκBβ (NFKBIB) isoforms (IkBb-1 and IkBb-2). IL-1β stimulation causes rapid degradation of IκBα within 2 h but causes a decrease in IkBb-1 without full recovery by 2 h, and has little effect on IkBb-2. IkBb-2 was found in both cytosolic and nuclear protein fractions, and its nuclear localization suggests a role in protecting NF-κB from inactivation by IκBα to maintain NF-κB-mediated gene transcription.\",\n      \"method\": \"Western blot, subcellular fractionation, quantitative protein analysis\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, fractionation with functional inference but no direct functional manipulation of NFKBIB\",\n      \"pmids\": [\"12651903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In murine macrophages and fibroblasts, IκBβ (NFKBIB) is necessary and sufficient for LPS-induced expression of a select subset of pro-inflammatory genes (IL1β, IL6, IL12β). Low-dose NFκB inhibitors specifically attenuate LPS-induced IκBβ degradation and the expression of these target genes. IκBβ overexpressing mice show attenuated LPS-induced signaling and cytokine expression. A cell-permeable peptide containing the cRel nuclear localization sequence attenuated IL6 expression, confirming that IκBβ acts via its NFκB subunit binding partner cRel.\",\n      \"method\": \"Gain- and loss-of-function experiments (transgenic overexpressing mice, siRNA/genetic KO), pharmacological inhibition, cell-permeable peptide treatment, cytokine measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transgenic mice, KO, pharmacological inhibitor, cell-permeable peptide), gain- and loss-of-function with defined molecular phenotype, single lab but comprehensive\",\n      \"pmids\": [\"25908863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-20a directly targets the 3' UTR of NFKBIB mRNA (confirmed by luciferase 3'UTR reporter and ago-immunoprecipitation), reducing NFKBIB (IκBβ) protein levels, which leads to upregulation of p65 and downstream targets livin and survivin, thereby activating NF-κB signaling and contributing to cisplatin resistance in gastric cancer cells.\",\n      \"method\": \"3' UTR luciferase reporter assay, ago-immunoprecipitation, miRNA mimic/inhibitor transfection, Western blot, apoptosis assay\",\n      \"journal\": \"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter and ago-IP are orthogonal methods validating direct miR-20a targeting of NFKBIB mRNA; single lab\",\n      \"pmids\": [\"26286834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-4776 directly targets NFKBIB mRNA (confirmed by ago-immunoprecipitation and 3' UTR luciferase assay) in bronchial epithelial cells. Upon influenza A virus (IAV) infection, miR-4776 is upregulated within 1 h, causing decreased NFKBIB expression and consequently increased NF-κB activity. Overexpression of NFKBIB protein in IAV-infected cells led to lower levels of IAV, indicating NFKBIB suppresses viral replication through NF-κB modulation.\",\n      \"method\": \"Ago-immunoprecipitation, 3' UTR luciferase assay, miRNA mimic transfection, NFKBIB overexpression, viral load measurement\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (ago-IP and 3'UTR luciferase) confirm direct targeting; functional overexpression experiment with defined viral output phenotype; single lab\",\n      \"pmids\": [\"28448456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nuclear KIT binds directly to the promoter of NFKBIB by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, driving enhanced NFKBIB protein expression. Downregulation of NFKBIB by siRNA leads to RELA nuclear translocation, which in turn binds the KIT promoter and reduces KIT transcription/expression and GIST cell viability, establishing a nuclear KIT→NFKBIB→RELA→KIT autoregulatory loop in imatinib-resistant gastrointestinal stromal tumors.\",\n      \"method\": \"ChIP sequencing, ChIP assay, siRNA knockdown, RELA overexpression, promoter-reporter assay, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-seq and ChIP assay directly demonstrate nuclear KIT binding to NFKBIB promoter; siRNA and overexpression provide functional validation; xenograft in vivo confirmation; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"31363162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IKBB (NFKBIB) acts as a tumor suppressor in nasopharyngeal carcinoma (NPC) by inhibiting NF-κB pathway activity. IKBB overexpression suppresses tumor formation, cell migration, and angiogenesis in NPC cells, and downregulates pro-angiogenic factors (Rantes, Upar, IL6, IL8) at the transcriptional level. Functional complementation via microcell-mediated chromosome transfer identified IKBB as a putative TSG, and its suppressive role is likely mediated by crosstalk with the Akt/Gsk3β signaling pathway.\",\n      \"method\": \"Microcell-mediated chromosome transfer, functional complementation, migration assay, angiogenesis assay, tumor formation assay, gene expression analysis\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation and multiple cellular phenotype assays; crosstalk with Akt/Gsk3β pathway is mechanistically proposed but supported by expression data; single lab\",\n      \"pmids\": [\"26227166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LINC01578 (a chromatin-bound lncRNA) binds directly to the NFKBIB promoter and recruits EZH2 to the NFKBIB promoter, repressing NFKBIB expression via epigenetic silencing, thereby activating NF-κB signaling and promoting colon cancer metastasis through a positive feedback loop with the NF-κB/YY1 axis.\",\n      \"method\": \"ChIP assay, RNA pulldown, promoter reporter assay, siRNA/overexpression, in vivo metastasis model\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and RNA pulldown confirm direct LINC01578 binding to NFKBIB promoter and EZH2 recruitment; functional consequence validated in vivo; single lab\",\n      \"pmids\": [\"33040438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TSPAN1 inhibits NPC metastasis by directly interacting with IKBB (NFKBIB) protein, and this interaction is essential for preventing overactivation of the NF-κB pathway in NPC cells.\",\n      \"method\": \"Co-immunoprecipitation (protein interaction), in vitro migration/invasion assay, in vivo metastasis assay, NF-κB pathway reporter/expression analysis\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP demonstrating TSPAN1-IKBB interaction; mechanistic follow-up is limited to NF-κB pathway expression changes; single lab\",\n      \"pmids\": [\"38135697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Using the IκB- (Nfkbia+/-Nfkbib-/-Nfkbie-/-) mouse model with elevated NFκB activity, population dynamics modeling combined with scRNA-seq revealed that elevated NFκB signaling (involving NFKBIB loss) drives myeloid bias in hematopoiesis not only through HSC differentiation bias but also through increased expansion of early myeloid-primed progenitors, an effect conserved when wild-type HSPCs are transplanted into IκB- recipients, indicating the bone marrow microenvironment is sufficient to drive this phenotype.\",\n      \"method\": \"Triple knockout mouse model (Nfkbia+/-Nfkbib-/-Nfkbie-/-), scRNA-seq, differential equation population dynamics modeling, bone marrow transplantation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model with scRNA-seq and transplantation experiments provide mechanistic pathway placement; modeling adds quantitative insight; NFKBIB contribution is inferred from compound knockout context rather than isolated\",\n      \"pmids\": [\"39791596\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NFKBIB (IκBβ) functions as an inhibitor of NF-κB signaling by sequestering NF-κB in the cytoplasm; it is selectively required for LPS-induced expression of a subset of pro-inflammatory genes (IL1β, IL6, IL12β) acting through the cRel subunit, its nuclear isoform can maintain persistent NF-κB activity, its promoter is a direct target of nuclear KIT (establishing a KIT→NFKBIB→RELA→KIT autoregulatory loop in GISTs), it is directly targeted post-transcriptionally by miR-20a and miR-4776 (modulating NF-κB activity and viral replication/chemoresistance), it is epigenetically silenced by EZH2 recruited via lncRNA LINC01578, and it physically interacts with TSPAN1 to suppress NF-κB-driven metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NFKBIB (IκBβ) is a cytoplasmic inhibitor of NF-κB signaling that, distinct from a generic NF-κB brake, is selectively required for the LPS-induced expression of a defined subset of pro-inflammatory genes — IL1β, IL6, and IL12β — acting through its NF-κB subunit binding partner cRel rather than through global NF-κB suppression [#2]. Its activity is set by regulated degradation: low-dose NF-κB inhibitors specifically attenuate LPS-induced IκBβ degradation and the resulting cytokine output, and IκBβ overexpression dampens LPS-driven signaling in vivo [#2]. Across epithelial and tumor contexts NFKBIB behaves as a restraint on NF-κB, and its loss activates the pathway: it suppresses influenza A virus replication via NF-κB modulation [#4], acts as a tumor suppressor in nasopharyngeal carcinoma where it limits migration, angiogenesis, and pro-angiogenic gene expression [#6], and physically interacts with TSPAN1 to prevent NF-κB overactivation and metastasis [#8]. NFKBIB levels are controlled at multiple regulatory layers — direct post-transcriptional targeting by miR-20a and miR-4776, which lowers IκBβ protein and de-represses NF-κB to drive chemoresistance and viral replication [#3, #4]; transcriptional induction by nuclear KIT binding its promoter to form a KIT→NFKBIB→RELA→KIT autoregulatory loop in imatinib-resistant GISTs [#5]; and epigenetic silencing through LINC01578-mediated recruitment of EZH2 to its promoter, activating NF-κB to promote colon cancer metastasis [#7]. At the organismal level, compound IκB loss including Nfkbib drives myeloid-biased hematopoiesis via both progenitor expansion and microenvironmental effects [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Before any inflammatory role was known, NFKBIB was first captured as a thyroid-hormone-receptor-interacting protein, an early but isolated lead on its protein-interaction behavior.\",\n      \"evidence\": \"Yeast two-hybrid interaction trap with LexA fusion reporter assay, isolating NFKBIB as TRIP9 binding TRβ ligand-binding domain\",\n      \"pmids\": [\"7776974\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single yeast two-hybrid with no biochemical reconstitution in mammalian cells\", \"Relationship of this TR interaction to NF-κB inhibition never established\", \"No follow-up confirming functional relevance\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The question of whether IκBβ acts only as a cytoplasmic sequestrant was addressed by showing distinct isoform behavior, with a nuclear-localized isoform implicated in sustaining rather than terminating NF-κB transcription.\",\n      \"evidence\": \"Western blot, subcellular fractionation and quantitative protein analysis of IκBβ isoforms in IL-1β-stimulated human amnion\",\n      \"pmids\": [\"12651903\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Nuclear role inferred from localization, not functional manipulation\", \"Isoform-specific functions not dissected genetically\", \"No direct demonstration of NF-κB protection\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The central mechanistic advance defined IκBβ not as a generic inhibitor but as a selective, cRel-dependent requirement for a specific LPS-induced pro-inflammatory gene module.\",\n      \"evidence\": \"Transgenic overexpressing mice, genetic KO/siRNA, pharmacological NF-κB inhibition, and a cRel-NLS cell-permeable peptide with cytokine readout in macrophages and fibroblasts\",\n      \"pmids\": [\"25908863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of gene-subset selectivity not fully resolved\", \"Structural detail of IκBβ–cRel complex absent\", \"Degradation kinetics under different stimuli not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Post-transcriptional control of NFKBIB was established by showing a microRNA directly tunes IκBβ protein to set NF-κB output and chemoresistance.\",\n      \"evidence\": \"3'UTR luciferase reporter, ago-immunoprecipitation, miRNA mimic/inhibitor, Western blot and apoptosis assays in gastric cancer cells (miR-20a)\",\n      \"pmids\": [\"26286834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream livin/survivin link correlative\", \"Single lab, single cancer context\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"NFKBIB was placed as a tumor suppressor whose restoration suppresses NF-κB-driven migration and angiogenesis, broadening its role beyond inflammation.\",\n      \"evidence\": \"Microcell-mediated chromosome transfer, functional complementation, migration/angiogenesis/tumor-formation assays and gene expression in nasopharyngeal carcinoma\",\n      \"pmids\": [\"26227166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Akt/GSK3β crosstalk proposed from expression data, not mechanism\", \"Direct molecular target of suppression unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A second microRNA axis confirmed direct post-transcriptional silencing of NFKBIB and tied it to antiviral defense, with IκBβ restraining viral replication via NF-κB.\",\n      \"evidence\": \"Ago-immunoprecipitation, 3'UTR luciferase, miRNA mimic, NFKBIB overexpression and viral-load measurement in IAV-infected bronchial epithelial cells (miR-4776)\",\n      \"pmids\": [\"28448456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which NF-κB-dependent antiviral effectors mediate restraint unspecified\", \"Single cell system\", \"miR-4776 induction mechanism not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Transcriptional regulation of NFKBIB was uncovered as part of an autoregulatory circuit, showing nuclear KIT directly induces the NFKBIB promoter to constrain RELA in drug-resistant GIST.\",\n      \"evidence\": \"ChIP-seq, ChIP assay, siRNA knockdown, RELA overexpression, promoter-reporter and xenograft in imatinib-resistant gastrointestinal stromal tumors\",\n      \"pmids\": [\"31363162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the KIT→NFKBIB→RELA→KIT loop beyond GIST untested\", \"Direct KIT-NFKBIB promoter contact site not mapped at base resolution\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Epigenetic silencing emerged as a third regulatory layer, with a chromatin-bound lncRNA recruiting EZH2 to repress NFKBIB and unleash NF-κB-driven metastasis.\",\n      \"evidence\": \"ChIP, RNA pulldown, promoter reporter, siRNA/overexpression and in vivo metastasis model in colon cancer (LINC01578/EZH2)\",\n      \"pmids\": [\"33040438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Histone mark deposition at NFKBIB promoter not directly profiled\", \"Generalizability beyond colon cancer untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Compound IκB genetics placed NFKBIB loss in hematopoietic regulation, showing elevated NF-κB drives myeloid bias through both progenitor expansion and the bone marrow microenvironment.\",\n      \"evidence\": \"Nfkbia+/-Nfkbib-/-Nfkbie-/- mouse model with scRNA-seq, population dynamics modeling and bone marrow transplantation\",\n      \"pmids\": [\"39791596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NFKBIB contribution inferred from compound knockout, not isolated\", \"Cell-autonomous vs microenvironmental contributions of NFKBIB specifically not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A direct protein partner restraining NF-κB was identified, with TSPAN1 binding IκBβ to prevent pathway overactivation and metastasis.\",\n      \"evidence\": \"Co-immunoprecipitation, migration/invasion assays, in vivo metastasis assay and NF-κB pathway analysis in nasopharyngeal carcinoma\",\n      \"pmids\": [\"38135697\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation or structural mapping\", \"Mechanism of how TSPAN1 binding affects IκBβ activity unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple regulatory layers (degradation, miRNA, transcriptional, epigenetic, protein interaction) are integrated to set IκBβ levels in a given cell, and the structural basis for its cRel-selective gene control, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of IκBβ–cRel selectivity\", \"No unified model coupling NFKBIB transcriptional and post-transcriptional control\", \"Isoform-specific nuclear function not mechanistically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 6]},\n      {\"term_id\": \"GO:0140110\", \"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-168256\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"REL\", \"RELA\", \"KIT\", \"TSPAN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}