{"gene":"NFKBIZ","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2000,"finding":"MAIL (NFKBIZ) is a novel nuclear IκB protein with ankyrin repeats whose ectopic expression potentiates LPS-induced IL-6 mRNA expression and secretion in Swiss 3T3 cells; it localizes to the nucleus when ectopically expressed.","method":"Ectopic expression in Swiss 3T3 cells, RT-PCR, ELISA, immunolocalization","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, gain-of-function with defined cytokine phenotype and nuclear localization, but no binding partner identified in this study","pmids":["11086164"],"is_preprint":false},{"year":2001,"finding":"The mouse Mail gene consists of 14 exons spanning ~30 kb, maps to chromosome 16C1.2-C1.3, contains NF-κB and NF-IL6 binding sites in its proximal promoter, and this promoter region drives high-level reporter gene expression in LPS-stimulated transfected cells.","method":"Genomic cloning, Southern hybridization, FISH, primer extension, promoter-reporter assay","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (FISH, primer extension, reporter assay), single lab","pmids":["11797098"],"is_preprint":false},{"year":2002,"finding":"LPS-induced MAIL (NFKBIZ) mRNA expression is mediated at least in part through TLR4: neutralizing anti-TLR4 antibody attenuated MAIL induction in PMA-differentiated U937 cells, and TLR4 missense-mutant mice showed reduced in vivo MAIL induction in the spleen.","method":"Neutralizing antibody treatment, comparison of TLR4-mutant vs. wild-type mice, RT-PCR","journal":"The Journal of veterinary medical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (TLR4 mutant) plus antibody blockade, single lab, two orthogonal approaches","pmids":["12069074"],"is_preprint":false},{"year":2003,"finding":"LPS induces MAIL (NFKBIZ) expression predominantly in B-lymphocytes and macrophages (not T-lymphocytes, fibroblasts, or endothelial cells) in vivo and in vitro; the predominant isoform expressed is the long splice variant MAIL-L; inflammatory cytokines IL-1, IL-6, and TNF also induce MAIL in cultured cells.","method":"In situ hybridization, immunohistochemistry, Northern blot, Western blot, cell culture stimulation assays","journal":"Archives of histology and cytology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ISH, IHC, Northern, Western), single lab","pmids":["12703554"],"is_preprint":false},{"year":2004,"finding":"MAIL-deficient (Mail−/−) mice develop spontaneous atopic dermatitis-like skin lesions with elevated serum IgE, inflammatory cell infiltration, and markedly elevated expression of chemokines such as TARC, indicating MAIL is essential for homeostatic regulation of skin immunity and keratinocyte function.","method":"Targeted gene disruption (knockout mice), histopathology, ELISA, RT-PCR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with well-defined cellular phenotype, replicated in multiple subsequent studies","pmids":["15491998"],"is_preprint":false},{"year":2004,"finding":"MAIL (NFKBIZ) promoter activity is strongly regulated by NF-κB binding at the −229 to −220 bp site; CREB also partly regulates expression; overexpression of MAIL protein suppresses its own LPS-induced promoter activity, indicating an autoregulatory negative feedback loop.","method":"Promoter deletion/mutation analysis, EMSA/binding assay, luciferase reporter assay, overexpression in RAW264 cells","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis plus binding assay plus reporter assay, single lab, multiple orthogonal methods","pmids":["15527973"],"is_preprint":false},{"year":2007,"finding":"Constitutive MAIL (NFKBIZ) expression in epidermal keratinocytes is controlled at least in part by NF-κB: the NF-κB inhibitor Bay11-7082 and IκBαM supersuppressor significantly downregulated MAIL expression; LPS did not induce MAIL in keratinocytes, but IL-1 did, suggesting LPS-specific repressive mechanisms in this cell type.","method":"Pharmacological NF-κB inhibition, dominant-negative IκBαM overexpression, RT-PCR, immunohistochemistry in primary keratinocytes and PAM212 cell line","journal":"The Journal of veterinary medical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal inhibition strategies (small molecule + genetic), single lab","pmids":["17409644"],"is_preprint":false},{"year":2008,"finding":"The FUS-DDIT3 fusion oncoprotein colocalizes with NFKBIZ in nuclear structures and physically interacts with the C-terminal domain of NFKBIZ by co-immunoprecipitation; this interaction is associated with upregulation of NF-κB-controlled genes (including IL8) in myxoid liposarcoma cells.","method":"Immunoprecipitation, co-localization by immunofluorescence, chromatin immunoprecipitation, IL8 promoter reporter assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping, ChIP and reporter assay, single lab","pmids":["18850010"],"is_preprint":false},{"year":2009,"finding":"Human MAIL-L (80 kDa isoform) localizes to the nucleus, binds the p50 subunit of NF-κB, and increases IL-6 promoter activity in a C/EBPβ-, NF-κB-, and AP-1-dependent fashion; siRNA-mediated MAIL knockdown significantly decreases IL-6 production in THP-1 cells and primary monocytes; MAIL protein expression is suppressed during monocyte-to-macrophage differentiation, correlating with reduced IL-6 output.","method":"Co-immunoprecipitation (MAIL-L with p50), luciferase promoter assay, siRNA knockdown, Western blot, ELISA, immunolocalization","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — binding partner identified by co-IP, functional consequence confirmed by siRNA knockdown and reporter assay, multiple orthogonal methods, single lab","pmids":["19783680"],"is_preprint":false},{"year":2015,"finding":"Nfkbiz-deficient keratinocytes are hypoproliferative; expression of differentiation markers K10 and filaggrin is reduced in Nfkbiz−/− skin, while NF-κB subcellular localization and transcriptional activity are unchanged in Nfkbiz−/− keratinocytes, indicating Nfkbiz controls keratinocyte proliferation and differentiation through NF-κB-independent mechanisms.","method":"Knockout mouse analysis, Ki-67 immunohistochemistry, TUNEL assay, Western blot for NF-κB subunit localization, NF-κB reporter assay","journal":"The Japanese journal of veterinary research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotypes and NF-κB pathway exclusion by reporter assay, single lab","pmids":["26563030"],"is_preprint":false},{"year":2015,"finding":"IFN-γ induces Nfkbiz expression in keratinocytes via a JAK1-dependent mechanism requiring the ISRE element in the Nfkbiz promoter; IFN-γ and IL-1 show synergism in Nfkbiz induction requiring both JAK1 and NF-κB.","method":"Promoter analysis (ISRE deletion), selective kinase inhibitors (JAK1, NF-κB), RT-PCR in primary keratinocytes","journal":"Biomedical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter element deletion combined with pharmacological inhibition, single lab","pmids":["25876660"],"is_preprint":false},{"year":2017,"finding":"Nfkbiz−/− mice with spontaneous dermatitis show decreased bacterial diversity and markedly expanded Staphylococcus xylosus on skin; antibiotic treatment ameliorates skin inflammation; topical application of S. xylosus to Nfkbiz−/− mice expands IL-17A-secreting CD4+ T cells and elevates pro-inflammatory cytokines/chemokines, indicating Nfkbiz regulates the microbiota-skin immunity axis.","method":"Knockout mouse model, pyrosequencing of skin microbiome, antibiotic treatment experiment, topical bacterial application, flow cytometry, ELISA","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vivo experiments (antibiotic rescue, topical bacteria challenge) in KO model, single lab","pmids":["28740238"],"is_preprint":false},{"year":2020,"finding":"In human synovial fibroblasts, IL-17A selectively and dose-dependently induces NFKBIZ transcription; IκBζ (NFKBIZ) mediates the transcriptional synergy between TNF and IL-17A but not the response to TNF alone; IκBζ engages the NF-κB complex to drive expression of CXCL1, CXCL2, and CXCL3, promoting neutrophil and monocyte recruitment; CUX1 and NF-κB p65 co-mediate this response via a unique promoter motif.","method":"siRNA gene silencing (NFKBIZ, CUX1, STAT3, STAT4, LIFR, ELF3), time-series and dose-response transcriptomics, promoter motif analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA epistasis for multiple factors combined with transcriptomics dose-response, independently contextualized by motif analysis, single lab with multiple orthogonal methods","pmids":["32079724"],"is_preprint":false},{"year":2020,"finding":"miR-376b directly targets and suppresses NFKBIZ expression (confirmed by luciferase microRNA target reporter assay); NF-κB binds the miR-376b gene promoter upon LPS treatment (confirmed by ChIP); this constitutes a NF-κB/miR-376b/NFKBIZ negative feedback loop regulating renal tubular inflammation in septic AKI.","method":"Luciferase microRNA target reporter assay, ChIP assay, miR-376b mimic/inhibitor in vitro and in vivo, Western blot, ELISA","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct miRNA target validated by luciferase reporter, ChIP confirming upstream regulation, functional rescue in vivo, multiple orthogonal methods, single lab","pmids":["33328388"],"is_preprint":false},{"year":2021,"finding":"IκBζ (encoded by Nfkbiz) controls Lcn2 expression in sepsis: pharmacological inhibition of IκBζ largely abolished Lcn2 induction; Nfkbiz mRNA is rapidly induced then declines, while IκBζ protein remains elevated after CLP (but not LPS), indicating a CLP-specific mechanism extending IκBζ protein half-life.","method":"CLP and LPS animal models, IκBζ inhibitor treatment, RT-PCR, Western blot","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological inhibition with defined downstream target (Lcn2), two model comparisons, single lab","pmids":["33431705"],"is_preprint":false},{"year":2022,"finding":"NFKBIZ promoter is cooperatively activated by C/EBPβ (via an adjacent C/EBP-binding site) and STAT3 in response to IL-17A; STAT1 suppresses both C/EBPβ- and STAT3-driven NFKBIZ promoter activation independently of STAT1 Y701 phosphorylation; siRNA knockdown of C/EBPβ attenuates IL-17A-induced NFKBIZ upregulation.","method":"NFKBIZ promoter deletion/luciferase reporter assay, siRNA knockdown of C/EBPβ and STAT1, co-overexpression experiments in HaCaT cells, RT-PCR","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis combined with siRNA knockdown and overexpression, multiple transcription factors tested, single lab","pmids":["35537286"],"is_preprint":false},{"year":2024,"finding":"Regnase-1 (encoded by Zc3h12a) and regnase-3 (Zc3h12c) post-transcriptionally degrade Nfkbiz mRNA in hematopoietic stem and progenitor cells (HSPCs); loss of Reg1/Reg3 causes elevated Nfkbiz expression that drives myeloid-biased lineage output, as demonstrated by antisense oligonucleotide-mediated Nfkbiz mRNA stabilization and single-cell ATAC-seq showing Nfkbiz-dependent chromatin remodeling at myeloid gene loci.","method":"Reg1/Reg3 double-knockout mice, single-cell RNA-seq, single-cell ATAC-seq, antisense oligonucleotide (ASO) targeting Reg1/Reg3-mediated Nfkbiz degradation, bone marrow transplantation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo KO plus ASO gain-of-function plus scRNA-seq and scATAC-seq, multiple orthogonal methods establishing mechanistic pathway","pmids":["37922454"],"is_preprint":false},{"year":2024,"finding":"TRIM16 physically interacts with NFKBIZ and promotes its ubiquitination at the K48 site, targeting NFKBIZ for degradation; disruption of this interaction elevates NFKBIZ, mediates NF-κB signaling transduction, and contributes to sorafenib insensitivity in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, protein degradation assay, flow cytometry (apoptosis), Western blot, immunofluorescence, xenograft model","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying direct interaction and K48 ubiquitination site, functional consequence in vitro and in vivo, single lab","pmids":["38581570"],"is_preprint":false},{"year":2025,"finding":"Regnase-1 degrades Nfkbiz mRNA in intestinal epithelial cells; Regnase-1 deletion in enterocytes elevates Nfkbiz and enhances IL-17 signaling, promoting colon tumor growth in an Apc mouse model; Nfkbiz knockout abolishes the tumor-promoting effect of Regnase-1 deletion, establishing Nfkbiz as the epistatic effector downstream of Regnase-1 in this pathway.","method":"Intestinal epithelial-specific Regnase-1 knockout mouse (Apc model), Nfkbiz knockout mouse epistasis, transcriptome analysis, antibiotic and IL-17 neutralizing antibody rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (Nfkbiz KO rescues Regnase-1 KO phenotype), in vivo intervention rescue, transcriptomics, multiple orthogonal methods","pmids":["40460118"],"is_preprint":false},{"year":2019,"finding":"NFKBIZ mutations prevalent in ulcerative colitis epithelium are selected against during colorectal carcinogenesis; disruption of NFKBIZ in human colorectal cancer cells impairs cell competition, and tumor formation is significantly attenuated in Nfkbiz-mutant mice, indicating NFKBIZ exerts tumor-suppressive function in colorectal cancer.","method":"Mutational profiling of UC and CRC tissues, NFKBIZ disruption in human CRC cell lines (cell competition assay), Nfkbiz-mutant mouse tumor model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic disruption in human cells plus mouse tumor model, multiple orthogonal approaches, large patient cohort correlating with functional experiments","pmids":["31853061"],"is_preprint":false}],"current_model":"NFKBIZ (IκBζ/MAIL) encodes a nuclear IκB protein that is rapidly induced by LPS (via TLR4), IL-1, IL-17A, and IFN-γ through NF-κB-, STAT3-, and C/EBPβ-dependent promoter activation; it physically associates with the NF-κB p50 subunit in the nucleus to selectively amplify transcription of target genes including IL-6, CXCL1-3, and Lcn2, while being subject to post-transcriptional decay by regnase-1/3, miR-376b targeting, and TRIM16-mediated K48-linked ubiquitination; loss of NFKBIZ in mice causes atopic dermatitis-like disease and dysbiosis, and its expression acts as an epistatic effector of IL-17 signaling in intestinal epithelia and of lymphoid/myeloid lineage choice in hematopoietic progenitors."},"narrative":{"mechanistic_narrative":"NFKBIZ (MAIL/IκBζ) encodes an inducible nuclear IκB-family protein that, rather than inhibiting NF-κB in the cytoplasm, acts within the nucleus to selectively amplify a defined set of inflammatory transcripts [PMID:11086164, PMID:19783680]. Its expression is rapidly induced by TLR4-dependent LPS signaling, IL-1, IFN-γ, and IL-17A [PMID:12069074, PMID:25876660, PMID:32079724], with its own promoter integrating NF-κB binding [PMID:15527973], cooperative C/EBPβ and STAT3 activation, and STAT1-mediated suppression [PMID:35537286], plus a JAK1/ISRE-dependent IFN-γ arm [PMID:25876660]. Mechanistically, the long isoform localizes to the nucleus and binds the NF-κB p50 subunit to drive IL-6 promoter activity in a C/EBPβ-, NF-κB-, and AP-1-dependent manner [PMID:19783680]; in synovial fibroblasts it mediates TNF/IL-17A transcriptional synergy and, together with CUX1 and p65, induces CXCL1–3 to recruit neutrophils and monocytes [PMID:32079724]. NFKBIZ output is tightly constrained by multiple post-transcriptional and post-translational brakes: regnase-1/3-mediated mRNA decay [PMID:37922454, PMID:40460118], NF-κB-driven miR-376b feedback [PMID:33328388], and TRIM16-mediated K48 ubiquitination and degradation [PMID:38581570]. Loss of NFKBIZ in mice produces spontaneous atopic dermatitis-like skin disease with elevated IgE and chemokines [PMID:15491998] and skin dysbiosis with Staphylococcus xylosus expansion [PMID:28740238], while it independently controls keratinocyte proliferation and differentiation through NF-κB-independent mechanisms [PMID:26563030]. NFKBIZ also functions as an epistatic effector of IL-17 signaling in intestinal epithelium where its loss abolishes regnase-1-deletion-driven colon tumor growth [PMID:40460118], yet acts as a tumor suppressor selected against in colorectal carcinogenesis through effects on cell competition [PMID:31853061], and biases hematopoietic progenitors toward myeloid lineage output via chromatin remodeling at myeloid loci [PMID:37922454].","teleology":[{"year":2000,"claim":"Established NFKBIZ as a novel nuclear ankyrin-repeat IκB protein that, unexpectedly, potentiates rather than inhibits an inflammatory cytokine response, reframing the IκB family as containing positive transcriptional regulators.","evidence":"Ectopic expression in Swiss 3T3 cells with IL-6 readout and immunolocalization","pmids":["11086164"],"confidence":"Medium","gaps":["No nuclear binding partner identified","Mechanism of IL-6 potentiation undefined","Gain-of-function only"]},{"year":2002,"claim":"Identified the upstream receptor for inflammatory induction, showing NFKBIZ is induced by LPS through TLR4 in vivo and in cultured myeloid cells.","evidence":"Anti-TLR4 neutralizing antibody and TLR4-mutant mice with RT-PCR","pmids":["12069074"],"confidence":"Medium","gaps":["Does not map the downstream transcription factors","Cell-type specificity not resolved"]},{"year":2004,"claim":"Defined the in vivo physiological requirement for NFKBIZ, showing its loss causes spontaneous atopic dermatitis-like disease, establishing it as essential for homeostatic skin immunity.","evidence":"Targeted knockout mice with histopathology, IgE ELISA, chemokine RT-PCR","pmids":["15491998"],"confidence":"High","gaps":["Cellular mechanism linking loss to dermatitis unresolved","Does not separate keratinocyte-intrinsic from immune effects"]},{"year":2004,"claim":"Established autoregulatory promoter control, showing NF-κB drives NFKBIZ transcription while NFKBIZ protein represses its own promoter, creating negative feedback.","evidence":"Promoter mutagenesis, EMSA, luciferase reporter, overexpression in RAW264 cells","pmids":["15527973"],"confidence":"High","gaps":["Mechanism of autorepression not defined","CREB contribution only partial"]},{"year":2009,"claim":"Identified the direct molecular partner, demonstrating the nuclear long isoform binds NF-κB p50 and is required for IL-6 production, providing the mechanistic basis for selective transcriptional amplification.","evidence":"Co-IP of MAIL-L with p50, IL-6 promoter reporter, siRNA knockdown in THP-1 and primary monocytes","pmids":["19783680"],"confidence":"High","gaps":["Structural basis of p50 engagement unresolved","Genome-wide target set not defined"]},{"year":2015,"claim":"Revealed an NF-κB-independent function, showing NFKBIZ controls keratinocyte proliferation and differentiation without altering NF-κB localization or activity.","evidence":"Knockout keratinocyte analysis, Ki-67/TUNEL, NF-κB reporter and localization assays","pmids":["26563030"],"confidence":"Medium","gaps":["The NF-κB-independent effector mechanism is unidentified","Differentiation marker regulation not mechanistically traced"]},{"year":2015,"claim":"Extended the inducer repertoire and promoter logic, showing IFN-γ induces NFKBIZ via JAK1 and an ISRE element synergizing with IL-1/NF-κB.","evidence":"ISRE deletion, JAK1/NF-κB inhibitors, RT-PCR in primary keratinocytes","pmids":["25876660"],"confidence":"Medium","gaps":["Transcription factor binding the ISRE not directly identified","Synergy mechanism with IL-1 not resolved"]},{"year":2017,"claim":"Connected NFKBIZ loss to a microbiota-immunity axis, showing dysbiosis with S. xylosus expansion drives IL-17A+ T cell expansion and inflammation that antibiotics rescue.","evidence":"Knockout mice, skin microbiome pyrosequencing, antibiotic and topical bacteria challenge, flow cytometry","pmids":["28740238"],"confidence":"Medium","gaps":["Whether dysbiosis is cause or consequence of barrier defect","Epithelial-intrinsic role versus immune role not separated"]},{"year":2019,"claim":"Identified a tumor-suppressive function in colorectal epithelium, showing NFKBIZ mutations are selected against during carcinogenesis and its disruption impairs cell competition and tumor formation.","evidence":"UC/CRC mutational profiling, NFKBIZ disruption in human CRC cells, Nfkbiz-mutant mouse tumor model","pmids":["31853061"],"confidence":"High","gaps":["Cell-competition mechanism not molecularly defined","Apparent conflict with tumor-promoting roles in other contexts unresolved"]},{"year":2020,"claim":"Defined NFKBIZ as the effector of TNF/IL-17A transcriptional synergy, showing it engages NF-κB with CUX1 to selectively drive CXCL1-3 chemokine output and leukocyte recruitment.","evidence":"siRNA epistasis for multiple factors, dose-response transcriptomics, promoter motif analysis in synovial fibroblasts","pmids":["32079724"],"confidence":"High","gaps":["Direct CUX1-IκBζ-p65 complex assembly not biochemically reconstituted","Genome-wide IκBζ occupancy not mapped"]},{"year":2020,"claim":"Added a post-transcriptional brake, establishing a NF-κB/miR-376b/NFKBIZ negative feedback loop regulating inflammation in septic kidney injury.","evidence":"Luciferase miRNA target reporter, ChIP, miR-376b mimic/inhibitor in vitro and in vivo","pmids":["33328388"],"confidence":"High","gaps":["Contribution relative to other decay pathways unquantified","Tissue specificity of the loop not addressed"]},{"year":2021,"claim":"Revealed stimulus-specific stabilization of IκBζ protein, showing CLP (but not LPS) extends its half-life to sustain Lcn2 induction in sepsis.","evidence":"CLP versus LPS models, IκBζ inhibitor, RT-PCR and Western blot","pmids":["33431705"],"confidence":"Medium","gaps":["The molecular mechanism extending protein half-life is unknown","Lcn2 promoter engagement not directly shown"]},{"year":2024,"claim":"Established regnase-mediated mRNA decay as a lineage-determining control, showing regnase-1/3 degrade Nfkbiz to restrain myeloid-biased hematopoietic output via chromatin remodeling.","evidence":"Reg1/Reg3 double-KO mice, scRNA-seq, scATAC-seq, ASO-mediated Nfkbiz stabilization, bone marrow transplant","pmids":["37922454"],"confidence":"High","gaps":["How NFKBIZ directs chromatin remodeling at myeloid loci is undefined","Direct genomic targets in HSPCs not mapped"]},{"year":2024,"claim":"Identified a post-translational degradation route, showing TRIM16 ubiquitinates NFKBIZ at K48 for degradation and that loss of this control elevates NFKBIZ and confers sorafenib insensitivity in HCC.","evidence":"Co-IP, protein degradation assay, K48 ubiquitination mapping, xenograft","pmids":["38581570"],"confidence":"Medium","gaps":["Whether TRIM16 is the direct E3 ligase versus an adaptor not fully resolved","Physiological contexts of this regulation beyond HCC unknown"]},{"year":2025,"claim":"Demonstrated NFKBIZ as the epistatic effector of regnase-1/IL-17 signaling in colon tumorigenesis, since Nfkbiz knockout abolishes the tumor-promoting effect of enterocyte regnase-1 deletion.","evidence":"Enterocyte-specific Regnase-1 KO Apc mouse, Nfkbiz KO epistasis, transcriptomics, antibiotic and IL-17 neutralization rescue","pmids":["40460118"],"confidence":"High","gaps":["Reconciliation with tumor-suppressive role in colorectal cell competition unresolved","Downstream NFKBIZ transcriptional targets in this context not detailed"]},{"year":null,"claim":"How NFKBIZ can be both tumor-suppressive in colorectal cell competition and tumor-promoting downstream of IL-17/regnase-1 in the same epithelium remains unresolved, as does the structural basis of its selective transcriptional activation.","evidence":"","pmids":[],"confidence":"High","gaps":["Context-dependent opposing cancer roles unexplained","No structural model of the IκBζ-p50 transcriptional complex","Genome-wide direct target catalogue across cell types incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,8,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[7,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,12,16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,12,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,12,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,19,17]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[13,16,18]}],"complexes":[],"partners":["NFKB1","RELA","CEBPB","STAT3","CUX1","TRIM16","FUS-DDIT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BYH8","full_name":"NF-kappa-B inhibitor zeta","aliases":["I-kappa-B-zeta","IkB-zeta","IkappaBzeta","IL-1 inducible nuclear ankyrin-repeat protein","INAP","Molecule possessing ankyrin repeats induced by lipopolysaccharide","MAIL"],"length_aa":718,"mass_kda":78.1,"function":"Involved in regulation of NF-kappa-B transcription factor complexes (PubMed:16513645, PubMed:16622025). Inhibits NF-kappa-B activity without affecting its nuclear translocation upon stimulation (PubMed:16513645). Inhibits DNA-binding of RELA and NFKB1/p50, and of the NF-kappa-B p65-p50 heterodimer and the NF-kappa-B p50-p50 homodimer (PubMed:16513645). Also seems to activate NF-kappa-B-mediated transcription (PubMed:16622025). In vitro, upon association with NFKB1/p50 has transcriptional activation activity and, together with NFKB1/p50 and RELA, is recruited to LCN2 promoters (PubMed:16622025). Promotes transcription of LCN2 and DEFB4 (PubMed:16622025). Is recruited to IL-6 promoters and activates IL-6 but decreases TNF production in response to LPS (By similarity). Seems to be involved in the induction of inflammatory genes activated through TLR/IL-1 receptor signaling (By similarity). Involved in the induction of T helper 17 cells (Th17) differentiation upon recognition of antigen by T cell antigen receptor (TCR) (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BYH8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NFKBIZ","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NFKBIZ","total_profiled":1310},"omim":[{"mim_id":"618887","title":"NUCLEAR FACTOR KAPPA-B INHIBITOR, DELTA; NFKBID","url":"https://www.omim.org/entry/618887"},{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"612839","title":"TET METHYLCYTOSINE DIOXYGENASE 2; TET2","url":"https://www.omim.org/entry/612839"},{"mim_id":"608004","title":"NUCLEAR FACTOR KAPPA-B INHIBITOR, ZETA; NFKBIZ","url":"https://www.omim.org/entry/608004"},{"mim_id":"607043","title":"TRAF3-INTERACTING PROTEIN 2; TRAF3IP2","url":"https://www.omim.org/entry/607043"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Cytoplasmic bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone 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neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35371228","citation_count":4,"is_preprint":false},{"pmid":"21436932","id":"PMC_21436932","title":"Faculty and student expectations and perceptions of e-mail communication in a campus and distance doctor of pharmacy program.","date":"2010","source":"American journal of pharmaceutical education","url":"https://pubmed.ncbi.nlm.nih.gov/21436932","citation_count":4,"is_preprint":false},{"pmid":"28474337","id":"PMC_28474337","title":"Impact of predictive scoring model and e-mail messages on African American blood donors.","date":"2017","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/28474337","citation_count":4,"is_preprint":false},{"pmid":"15010226","id":"PMC_15010226","title":"Cloning of bovine MAIL and its mRNA expression in white blood cells of Holstein cows.","date":"2004","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/15010226","citation_count":3,"is_preprint":false},{"pmid":"32928187","id":"PMC_32928187","title":"Direct marketing in health and medicine: using direct mail, email marketing, and related communicative methods to engage patients.","date":"2020","source":"BMC health services research","url":"https://pubmed.ncbi.nlm.nih.gov/32928187","citation_count":3,"is_preprint":false},{"pmid":"21505395","id":"PMC_21505395","title":"The \"phone and mail\" system in a teledermatology service for chronic psychiatric patients.","date":"2011","source":"Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia","url":"https://pubmed.ncbi.nlm.nih.gov/21505395","citation_count":3,"is_preprint":false},{"pmid":"22734463","id":"PMC_22734463","title":"Cheek swabs, SNP chips, and CNVs: assessing the quality of copy number variant calls generated with subject-collected mail-in buccal brush DNA samples on a high-density genotyping microarray.","date":"2012","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22734463","citation_count":3,"is_preprint":false},{"pmid":"24319078","id":"PMC_24319078","title":"Assessing the potential of e-mail for communicating drug therapy recommendations to physicians in patients with heart failure and ventricular-assist devices.","date":"2013","source":"Journal of pharmacy practice","url":"https://pubmed.ncbi.nlm.nih.gov/24319078","citation_count":3,"is_preprint":false},{"pmid":"11857951","id":"PMC_11857951","title":"[Second malignancies following radiotherapy: an analysis of 54 cases accumulated by mail survey in Japan].","date":"2002","source":"Nihon Igaku Hoshasen Gakkai zasshi. Nippon acta radiologica","url":"https://pubmed.ncbi.nlm.nih.gov/11857951","citation_count":3,"is_preprint":false},{"pmid":"39322062","id":"PMC_39322062","title":"Assessing the association between common functional Nuclear Factor Kappa-b gene polymorphisms (NFKB1, NFKBIZ, NFKBIA) and Alzheimer´s disease.","date":"2024","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/39322062","citation_count":2,"is_preprint":false},{"pmid":"34890398","id":"PMC_34890398","title":"Diagnosis of Taenia solium infections based on \"mail order\" RNA-sequencing of single tapeworm egg isolates from stool samples.","date":"2021","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/34890398","citation_count":2,"is_preprint":false},{"pmid":"41513081","id":"PMC_41513081","title":"NFKBIZ mediates neuroprotection and maintains blood-brain barrier integrity in cerebral ischemia/reperfusion via STAT3-regulated Nrf2/ARE signaling.","date":"2026","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/41513081","citation_count":1,"is_preprint":false},{"pmid":"5907946","id":"PMC_5907946","title":"Mail-order chromosome analysis.","date":"1966","source":"Canadian Medical Association journal","url":"https://pubmed.ncbi.nlm.nih.gov/5907946","citation_count":1,"is_preprint":false},{"pmid":"40448937","id":"PMC_40448937","title":"You've got mail: comparing individuals who do and do not provide DNA saliva samples by mail in a study of severe alcohol use disorder.","date":"2025","source":"Alcohol and alcoholism (Oxford, Oxfordshire)","url":"https://pubmed.ncbi.nlm.nih.gov/40448937","citation_count":1,"is_preprint":false},{"pmid":"18404894","id":"PMC_18404894","title":"Cell phone e-mail as a means to collect information on pregnancy and delivery: a pilot study in Japan.","date":"2008","source":"Fukuoka igaku zasshi = Hukuoka acta medica","url":"https://pubmed.ncbi.nlm.nih.gov/18404894","citation_count":1,"is_preprint":false},{"pmid":"38143713","id":"PMC_38143713","title":"The Application of a Multi-Material Flexible Chain Mail for the Design of an Artificial Spinal Disc to Reproduce Natural Nonlinear and Anisotropic Rotational Behavior.","date":"2023","source":"3D printing and additive manufacturing","url":"https://pubmed.ncbi.nlm.nih.gov/38143713","citation_count":1,"is_preprint":false},{"pmid":"40683182","id":"PMC_40683182","title":"Peer-delivered mail-order self-collection and linkage to treatment for hepatitis C virus infection among users of a harm reduction service in Denmark.","date":"2025","source":"The International journal on drug policy","url":"https://pubmed.ncbi.nlm.nih.gov/40683182","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47225,"output_tokens":5284,"usd":0.110467,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13795,"output_tokens":4784,"usd":0.094287,"stage2_stop_reason":"end_turn"},"total_usd":0.204754,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"MAIL (NFKBIZ) is a novel nuclear IκB protein with ankyrin repeats whose ectopic expression potentiates LPS-induced IL-6 mRNA expression and secretion in Swiss 3T3 cells; it localizes to the nucleus when ectopically expressed.\",\n      \"method\": \"Ectopic expression in Swiss 3T3 cells, RT-PCR, ELISA, immunolocalization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, gain-of-function with defined cytokine phenotype and nuclear localization, but no binding partner identified in this study\",\n      \"pmids\": [\"11086164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The mouse Mail gene consists of 14 exons spanning ~30 kb, maps to chromosome 16C1.2-C1.3, contains NF-κB and NF-IL6 binding sites in its proximal promoter, and this promoter region drives high-level reporter gene expression in LPS-stimulated transfected cells.\",\n      \"method\": \"Genomic cloning, Southern hybridization, FISH, primer extension, promoter-reporter assay\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (FISH, primer extension, reporter assay), single lab\",\n      \"pmids\": [\"11797098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"LPS-induced MAIL (NFKBIZ) mRNA expression is mediated at least in part through TLR4: neutralizing anti-TLR4 antibody attenuated MAIL induction in PMA-differentiated U937 cells, and TLR4 missense-mutant mice showed reduced in vivo MAIL induction in the spleen.\",\n      \"method\": \"Neutralizing antibody treatment, comparison of TLR4-mutant vs. wild-type mice, RT-PCR\",\n      \"journal\": \"The Journal of veterinary medical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (TLR4 mutant) plus antibody blockade, single lab, two orthogonal approaches\",\n      \"pmids\": [\"12069074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LPS induces MAIL (NFKBIZ) expression predominantly in B-lymphocytes and macrophages (not T-lymphocytes, fibroblasts, or endothelial cells) in vivo and in vitro; the predominant isoform expressed is the long splice variant MAIL-L; inflammatory cytokines IL-1, IL-6, and TNF also induce MAIL in cultured cells.\",\n      \"method\": \"In situ hybridization, immunohistochemistry, Northern blot, Western blot, cell culture stimulation assays\",\n      \"journal\": \"Archives of histology and cytology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ISH, IHC, Northern, Western), single lab\",\n      \"pmids\": [\"12703554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MAIL-deficient (Mail−/−) mice develop spontaneous atopic dermatitis-like skin lesions with elevated serum IgE, inflammatory cell infiltration, and markedly elevated expression of chemokines such as TARC, indicating MAIL is essential for homeostatic regulation of skin immunity and keratinocyte function.\",\n      \"method\": \"Targeted gene disruption (knockout mice), histopathology, ELISA, RT-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with well-defined cellular phenotype, replicated in multiple subsequent studies\",\n      \"pmids\": [\"15491998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MAIL (NFKBIZ) promoter activity is strongly regulated by NF-κB binding at the −229 to −220 bp site; CREB also partly regulates expression; overexpression of MAIL protein suppresses its own LPS-induced promoter activity, indicating an autoregulatory negative feedback loop.\",\n      \"method\": \"Promoter deletion/mutation analysis, EMSA/binding assay, luciferase reporter assay, overexpression in RAW264 cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis plus binding assay plus reporter assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15527973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Constitutive MAIL (NFKBIZ) expression in epidermal keratinocytes is controlled at least in part by NF-κB: the NF-κB inhibitor Bay11-7082 and IκBαM supersuppressor significantly downregulated MAIL expression; LPS did not induce MAIL in keratinocytes, but IL-1 did, suggesting LPS-specific repressive mechanisms in this cell type.\",\n      \"method\": \"Pharmacological NF-κB inhibition, dominant-negative IκBαM overexpression, RT-PCR, immunohistochemistry in primary keratinocytes and PAM212 cell line\",\n      \"journal\": \"The Journal of veterinary medical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal inhibition strategies (small molecule + genetic), single lab\",\n      \"pmids\": [\"17409644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The FUS-DDIT3 fusion oncoprotein colocalizes with NFKBIZ in nuclear structures and physically interacts with the C-terminal domain of NFKBIZ by co-immunoprecipitation; this interaction is associated with upregulation of NF-κB-controlled genes (including IL8) in myxoid liposarcoma cells.\",\n      \"method\": \"Immunoprecipitation, co-localization by immunofluorescence, chromatin immunoprecipitation, IL8 promoter reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping, ChIP and reporter assay, single lab\",\n      \"pmids\": [\"18850010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human MAIL-L (80 kDa isoform) localizes to the nucleus, binds the p50 subunit of NF-κB, and increases IL-6 promoter activity in a C/EBPβ-, NF-κB-, and AP-1-dependent fashion; siRNA-mediated MAIL knockdown significantly decreases IL-6 production in THP-1 cells and primary monocytes; MAIL protein expression is suppressed during monocyte-to-macrophage differentiation, correlating with reduced IL-6 output.\",\n      \"method\": \"Co-immunoprecipitation (MAIL-L with p50), luciferase promoter assay, siRNA knockdown, Western blot, ELISA, immunolocalization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — binding partner identified by co-IP, functional consequence confirmed by siRNA knockdown and reporter assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"19783680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nfkbiz-deficient keratinocytes are hypoproliferative; expression of differentiation markers K10 and filaggrin is reduced in Nfkbiz−/− skin, while NF-κB subcellular localization and transcriptional activity are unchanged in Nfkbiz−/− keratinocytes, indicating Nfkbiz controls keratinocyte proliferation and differentiation through NF-κB-independent mechanisms.\",\n      \"method\": \"Knockout mouse analysis, Ki-67 immunohistochemistry, TUNEL assay, Western blot for NF-κB subunit localization, NF-κB reporter assay\",\n      \"journal\": \"The Japanese journal of veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotypes and NF-κB pathway exclusion by reporter assay, single lab\",\n      \"pmids\": [\"26563030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IFN-γ induces Nfkbiz expression in keratinocytes via a JAK1-dependent mechanism requiring the ISRE element in the Nfkbiz promoter; IFN-γ and IL-1 show synergism in Nfkbiz induction requiring both JAK1 and NF-κB.\",\n      \"method\": \"Promoter analysis (ISRE deletion), selective kinase inhibitors (JAK1, NF-κB), RT-PCR in primary keratinocytes\",\n      \"journal\": \"Biomedical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter element deletion combined with pharmacological inhibition, single lab\",\n      \"pmids\": [\"25876660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nfkbiz−/− mice with spontaneous dermatitis show decreased bacterial diversity and markedly expanded Staphylococcus xylosus on skin; antibiotic treatment ameliorates skin inflammation; topical application of S. xylosus to Nfkbiz−/− mice expands IL-17A-secreting CD4+ T cells and elevates pro-inflammatory cytokines/chemokines, indicating Nfkbiz regulates the microbiota-skin immunity axis.\",\n      \"method\": \"Knockout mouse model, pyrosequencing of skin microbiome, antibiotic treatment experiment, topical bacterial application, flow cytometry, ELISA\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vivo experiments (antibiotic rescue, topical bacteria challenge) in KO model, single lab\",\n      \"pmids\": [\"28740238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In human synovial fibroblasts, IL-17A selectively and dose-dependently induces NFKBIZ transcription; IκBζ (NFKBIZ) mediates the transcriptional synergy between TNF and IL-17A but not the response to TNF alone; IκBζ engages the NF-κB complex to drive expression of CXCL1, CXCL2, and CXCL3, promoting neutrophil and monocyte recruitment; CUX1 and NF-κB p65 co-mediate this response via a unique promoter motif.\",\n      \"method\": \"siRNA gene silencing (NFKBIZ, CUX1, STAT3, STAT4, LIFR, ELF3), time-series and dose-response transcriptomics, promoter motif analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA epistasis for multiple factors combined with transcriptomics dose-response, independently contextualized by motif analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32079724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-376b directly targets and suppresses NFKBIZ expression (confirmed by luciferase microRNA target reporter assay); NF-κB binds the miR-376b gene promoter upon LPS treatment (confirmed by ChIP); this constitutes a NF-κB/miR-376b/NFKBIZ negative feedback loop regulating renal tubular inflammation in septic AKI.\",\n      \"method\": \"Luciferase microRNA target reporter assay, ChIP assay, miR-376b mimic/inhibitor in vitro and in vivo, Western blot, ELISA\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct miRNA target validated by luciferase reporter, ChIP confirming upstream regulation, functional rescue in vivo, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33328388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IκBζ (encoded by Nfkbiz) controls Lcn2 expression in sepsis: pharmacological inhibition of IκBζ largely abolished Lcn2 induction; Nfkbiz mRNA is rapidly induced then declines, while IκBζ protein remains elevated after CLP (but not LPS), indicating a CLP-specific mechanism extending IκBζ protein half-life.\",\n      \"method\": \"CLP and LPS animal models, IκBζ inhibitor treatment, RT-PCR, Western blot\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological inhibition with defined downstream target (Lcn2), two model comparisons, single lab\",\n      \"pmids\": [\"33431705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NFKBIZ promoter is cooperatively activated by C/EBPβ (via an adjacent C/EBP-binding site) and STAT3 in response to IL-17A; STAT1 suppresses both C/EBPβ- and STAT3-driven NFKBIZ promoter activation independently of STAT1 Y701 phosphorylation; siRNA knockdown of C/EBPβ attenuates IL-17A-induced NFKBIZ upregulation.\",\n      \"method\": \"NFKBIZ promoter deletion/luciferase reporter assay, siRNA knockdown of C/EBPβ and STAT1, co-overexpression experiments in HaCaT cells, RT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis combined with siRNA knockdown and overexpression, multiple transcription factors tested, single lab\",\n      \"pmids\": [\"35537286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Regnase-1 (encoded by Zc3h12a) and regnase-3 (Zc3h12c) post-transcriptionally degrade Nfkbiz mRNA in hematopoietic stem and progenitor cells (HSPCs); loss of Reg1/Reg3 causes elevated Nfkbiz expression that drives myeloid-biased lineage output, as demonstrated by antisense oligonucleotide-mediated Nfkbiz mRNA stabilization and single-cell ATAC-seq showing Nfkbiz-dependent chromatin remodeling at myeloid gene loci.\",\n      \"method\": \"Reg1/Reg3 double-knockout mice, single-cell RNA-seq, single-cell ATAC-seq, antisense oligonucleotide (ASO) targeting Reg1/Reg3-mediated Nfkbiz degradation, bone marrow transplantation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo KO plus ASO gain-of-function plus scRNA-seq and scATAC-seq, multiple orthogonal methods establishing mechanistic pathway\",\n      \"pmids\": [\"37922454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM16 physically interacts with NFKBIZ and promotes its ubiquitination at the K48 site, targeting NFKBIZ for degradation; disruption of this interaction elevates NFKBIZ, mediates NF-κB signaling transduction, and contributes to sorafenib insensitivity in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, protein degradation assay, flow cytometry (apoptosis), Western blot, immunofluorescence, xenograft model\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying direct interaction and K48 ubiquitination site, functional consequence in vitro and in vivo, single lab\",\n      \"pmids\": [\"38581570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Regnase-1 degrades Nfkbiz mRNA in intestinal epithelial cells; Regnase-1 deletion in enterocytes elevates Nfkbiz and enhances IL-17 signaling, promoting colon tumor growth in an Apc mouse model; Nfkbiz knockout abolishes the tumor-promoting effect of Regnase-1 deletion, establishing Nfkbiz as the epistatic effector downstream of Regnase-1 in this pathway.\",\n      \"method\": \"Intestinal epithelial-specific Regnase-1 knockout mouse (Apc model), Nfkbiz knockout mouse epistasis, transcriptome analysis, antibiotic and IL-17 neutralizing antibody rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (Nfkbiz KO rescues Regnase-1 KO phenotype), in vivo intervention rescue, transcriptomics, multiple orthogonal methods\",\n      \"pmids\": [\"40460118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NFKBIZ mutations prevalent in ulcerative colitis epithelium are selected against during colorectal carcinogenesis; disruption of NFKBIZ in human colorectal cancer cells impairs cell competition, and tumor formation is significantly attenuated in Nfkbiz-mutant mice, indicating NFKBIZ exerts tumor-suppressive function in colorectal cancer.\",\n      \"method\": \"Mutational profiling of UC and CRC tissues, NFKBIZ disruption in human CRC cell lines (cell competition assay), Nfkbiz-mutant mouse tumor model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic disruption in human cells plus mouse tumor model, multiple orthogonal approaches, large patient cohort correlating with functional experiments\",\n      \"pmids\": [\"31853061\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NFKBIZ (IκBζ/MAIL) encodes a nuclear IκB protein that is rapidly induced by LPS (via TLR4), IL-1, IL-17A, and IFN-γ through NF-κB-, STAT3-, and C/EBPβ-dependent promoter activation; it physically associates with the NF-κB p50 subunit in the nucleus to selectively amplify transcription of target genes including IL-6, CXCL1-3, and Lcn2, while being subject to post-transcriptional decay by regnase-1/3, miR-376b targeting, and TRIM16-mediated K48-linked ubiquitination; loss of NFKBIZ in mice causes atopic dermatitis-like disease and dysbiosis, and its expression acts as an epistatic effector of IL-17 signaling in intestinal epithelia and of lymphoid/myeloid lineage choice in hematopoietic progenitors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NFKBIZ (MAIL/IκBζ) encodes an inducible nuclear IκB-family protein that, rather than inhibiting NF-κB in the cytoplasm, acts within the nucleus to selectively amplify a defined set of inflammatory transcripts [#0, #8]. Its expression is rapidly induced by TLR4-dependent LPS signaling, IL-1, IFN-γ, and IL-17A [#2, #10, #12], with its own promoter integrating NF-κB binding [#5], cooperative C/EBPβ and STAT3 activation, and STAT1-mediated suppression [#15], plus a JAK1/ISRE-dependent IFN-γ arm [#10]. Mechanistically, the long isoform localizes to the nucleus and binds the NF-κB p50 subunit to drive IL-6 promoter activity in a C/EBPβ-, NF-κB-, and AP-1-dependent manner [#8]; in synovial fibroblasts it mediates TNF/IL-17A transcriptional synergy and, together with CUX1 and p65, induces CXCL1–3 to recruit neutrophils and monocytes [#12]. NFKBIZ output is tightly constrained by multiple post-transcriptional and post-translational brakes: regnase-1/3-mediated mRNA decay [#16, #18], NF-κB-driven miR-376b feedback [#13], and TRIM16-mediated K48 ubiquitination and degradation [#17]. Loss of NFKBIZ in mice produces spontaneous atopic dermatitis-like skin disease with elevated IgE and chemokines [#4] and skin dysbiosis with Staphylococcus xylosus expansion [#11], while it independently controls keratinocyte proliferation and differentiation through NF-κB-independent mechanisms [#9]. NFKBIZ also functions as an epistatic effector of IL-17 signaling in intestinal epithelium where its loss abolishes regnase-1-deletion-driven colon tumor growth [#18], yet acts as a tumor suppressor selected against in colorectal carcinogenesis through effects on cell competition [#19], and biases hematopoietic progenitors toward myeloid lineage output via chromatin remodeling at myeloid loci [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established NFKBIZ as a novel nuclear ankyrin-repeat IκB protein that, unexpectedly, potentiates rather than inhibits an inflammatory cytokine response, reframing the IκB family as containing positive transcriptional regulators.\",\n      \"evidence\": \"Ectopic expression in Swiss 3T3 cells with IL-6 readout and immunolocalization\",\n      \"pmids\": [\"11086164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No nuclear binding partner identified\", \"Mechanism of IL-6 potentiation undefined\", \"Gain-of-function only\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the upstream receptor for inflammatory induction, showing NFKBIZ is induced by LPS through TLR4 in vivo and in cultured myeloid cells.\",\n      \"evidence\": \"Anti-TLR4 neutralizing antibody and TLR4-mutant mice with RT-PCR\",\n      \"pmids\": [\"12069074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not map the downstream transcription factors\", \"Cell-type specificity not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the in vivo physiological requirement for NFKBIZ, showing its loss causes spontaneous atopic dermatitis-like disease, establishing it as essential for homeostatic skin immunity.\",\n      \"evidence\": \"Targeted knockout mice with histopathology, IgE ELISA, chemokine RT-PCR\",\n      \"pmids\": [\"15491998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular mechanism linking loss to dermatitis unresolved\", \"Does not separate keratinocyte-intrinsic from immune effects\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established autoregulatory promoter control, showing NF-κB drives NFKBIZ transcription while NFKBIZ protein represses its own promoter, creating negative feedback.\",\n      \"evidence\": \"Promoter mutagenesis, EMSA, luciferase reporter, overexpression in RAW264 cells\",\n      \"pmids\": [\"15527973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of autorepression not defined\", \"CREB contribution only partial\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the direct molecular partner, demonstrating the nuclear long isoform binds NF-κB p50 and is required for IL-6 production, providing the mechanistic basis for selective transcriptional amplification.\",\n      \"evidence\": \"Co-IP of MAIL-L with p50, IL-6 promoter reporter, siRNA knockdown in THP-1 and primary monocytes\",\n      \"pmids\": [\"19783680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of p50 engagement unresolved\", \"Genome-wide target set not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed an NF-κB-independent function, showing NFKBIZ controls keratinocyte proliferation and differentiation without altering NF-κB localization or activity.\",\n      \"evidence\": \"Knockout keratinocyte analysis, Ki-67/TUNEL, NF-κB reporter and localization assays\",\n      \"pmids\": [\"26563030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The NF-κB-independent effector mechanism is unidentified\", \"Differentiation marker regulation not mechanistically traced\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the inducer repertoire and promoter logic, showing IFN-γ induces NFKBIZ via JAK1 and an ISRE element synergizing with IL-1/NF-κB.\",\n      \"evidence\": \"ISRE deletion, JAK1/NF-κB inhibitors, RT-PCR in primary keratinocytes\",\n      \"pmids\": [\"25876660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor binding the ISRE not directly identified\", \"Synergy mechanism with IL-1 not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected NFKBIZ loss to a microbiota-immunity axis, showing dysbiosis with S. xylosus expansion drives IL-17A+ T cell expansion and inflammation that antibiotics rescue.\",\n      \"evidence\": \"Knockout mice, skin microbiome pyrosequencing, antibiotic and topical bacteria challenge, flow cytometry\",\n      \"pmids\": [\"28740238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether dysbiosis is cause or consequence of barrier defect\", \"Epithelial-intrinsic role versus immune role not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a tumor-suppressive function in colorectal epithelium, showing NFKBIZ mutations are selected against during carcinogenesis and its disruption impairs cell competition and tumor formation.\",\n      \"evidence\": \"UC/CRC mutational profiling, NFKBIZ disruption in human CRC cells, Nfkbiz-mutant mouse tumor model\",\n      \"pmids\": [\"31853061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-competition mechanism not molecularly defined\", \"Apparent conflict with tumor-promoting roles in other contexts unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined NFKBIZ as the effector of TNF/IL-17A transcriptional synergy, showing it engages NF-κB with CUX1 to selectively drive CXCL1-3 chemokine output and leukocyte recruitment.\",\n      \"evidence\": \"siRNA epistasis for multiple factors, dose-response transcriptomics, promoter motif analysis in synovial fibroblasts\",\n      \"pmids\": [\"32079724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CUX1-IκBζ-p65 complex assembly not biochemically reconstituted\", \"Genome-wide IκBζ occupancy not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Added a post-transcriptional brake, establishing a NF-κB/miR-376b/NFKBIZ negative feedback loop regulating inflammation in septic kidney injury.\",\n      \"evidence\": \"Luciferase miRNA target reporter, ChIP, miR-376b mimic/inhibitor in vitro and in vivo\",\n      \"pmids\": [\"33328388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution relative to other decay pathways unquantified\", \"Tissue specificity of the loop not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed stimulus-specific stabilization of IκBζ protein, showing CLP (but not LPS) extends its half-life to sustain Lcn2 induction in sepsis.\",\n      \"evidence\": \"CLP versus LPS models, IκBζ inhibitor, RT-PCR and Western blot\",\n      \"pmids\": [\"33431705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular mechanism extending protein half-life is unknown\", \"Lcn2 promoter engagement not directly shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established regnase-mediated mRNA decay as a lineage-determining control, showing regnase-1/3 degrade Nfkbiz to restrain myeloid-biased hematopoietic output via chromatin remodeling.\",\n      \"evidence\": \"Reg1/Reg3 double-KO mice, scRNA-seq, scATAC-seq, ASO-mediated Nfkbiz stabilization, bone marrow transplant\",\n      \"pmids\": [\"37922454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NFKBIZ directs chromatin remodeling at myeloid loci is undefined\", \"Direct genomic targets in HSPCs not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a post-translational degradation route, showing TRIM16 ubiquitinates NFKBIZ at K48 for degradation and that loss of this control elevates NFKBIZ and confers sorafenib insensitivity in HCC.\",\n      \"evidence\": \"Co-IP, protein degradation assay, K48 ubiquitination mapping, xenograft\",\n      \"pmids\": [\"38581570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRIM16 is the direct E3 ligase versus an adaptor not fully resolved\", \"Physiological contexts of this regulation beyond HCC unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated NFKBIZ as the epistatic effector of regnase-1/IL-17 signaling in colon tumorigenesis, since Nfkbiz knockout abolishes the tumor-promoting effect of enterocyte regnase-1 deletion.\",\n      \"evidence\": \"Enterocyte-specific Regnase-1 KO Apc mouse, Nfkbiz KO epistasis, transcriptomics, antibiotic and IL-17 neutralization rescue\",\n      \"pmids\": [\"40460118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with tumor-suppressive role in colorectal cell competition unresolved\", \"Downstream NFKBIZ transcriptional targets in this context not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NFKBIZ can be both tumor-suppressive in colorectal cell competition and tumor-promoting downstream of IL-17/regnase-1 in the same epithelium remains unresolved, as does the structural basis of its selective transcriptional activation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-dependent opposing cancer roles unexplained\", \"No structural model of the IκBζ-p50 transcriptional complex\", \"Genome-wide direct target catalogue across cell types incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 8, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 12, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 12, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 12, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 19, 17]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [13, 16, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NFKB1\", \"RELA\", \"CEBPB\", \"STAT3\", \"CUX1\", \"TRIM16\", \"FUS-DDIT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}