Affinage

NFKB2

Nuclear factor NF-kappa-B p100 subunit · UniProt Q00653

Length
900 aa
Mass
96.7 kDa
Annotated
2026-04-29
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NFKB2 encodes the p100 precursor, which serves dual roles as an IκB-like cytoplasmic inhibitor that sequesters Rel family members (particularly RelB) via its C-terminal ankyrin repeats, and as the precursor for the p52 transcription factor subunit generated by NIK/IKKα-dependent, ubiquitin-proteasome-mediated co-translational processing (PMID:8458581, PMID:12374738, PMID:10597218). The processed p52 subunit forms transcriptionally active heterodimers—principally with RelB—that translocate to the nucleus and drive expression of target genes including CXCL12, EZH2, skp2, and CRH, while also exerting context-dependent repression through recruitment of HDAC1 or HDAC4 to promoters such as cyclin D1 (PMID:12808109, PMID:26455434, PMID:22287708, PMID:26307012). The abundance and processing of p100 are regulated by multiple E3 ubiquitin ligases (SCFβ-TrCP, SCFFbw7, KPC1), kinases (NIK, IKKα, GSK-3β), and the TRIM14/USP14 deubiquitinase axis that protects p100 from autophagic degradation (PMID:10835356, PMID:22708077, PMID:25860612, PMID:31921549). Heterozygous germline mutations disrupting the C-terminal degron of p100 block its processing to p52, preserve its IκB function, cause thymic medullary hypoplasia and increased T cell self-reactivity, and establish NFKB2 as a genetic cause of common variable immunodeficiency (CVID) and autoimmunity (PMID:24140114, PMID:33107914).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1992 High

    Identification of NFKB2 as encoding a p100 precursor with an N-terminal Rel homology domain and C-terminal ankyrin repeats established the gene's dual-function architecture—a DNA-binding transcription factor (p52) embedded within an IκB-like inhibitor.

    Evidence cDNA cloning, in vitro translation, EMSA, co-immunoprecipitation, and reporter assays in transfected cells

    PMID:1531086

    Open questions at the time
    • Processing mechanism from p100 to p52 unknown
    • Physiological stimuli triggering processing not identified
    • In vivo relevance not yet tested
  2. 1993 High

    Demonstration that p100's ankyrin repeat domain functions as an IκB by retaining Rel proteins (p65, c-Rel, RelB) in the cytoplasm, and that p52 heterodimers with p65 bind κB DNA with high affinity and activate transcription, defined the two functional states of the NFKB2 gene product.

    Evidence Scatchard binding analysis, in vitro transcription, co-IP with cytoplasmic retention assays, deletion mutagenesis across multiple Rel partners

    PMID:8334994 PMID:8441377 PMID:8458581

    Open questions at the time
    • Kinase(s) triggering p100 processing unknown
    • Protease/proteasome involvement not yet demonstrated
    • RelB-specific inhibition by p100 not yet established
  3. 1995 Medium

    The finding that the p100 C-terminal domain (IκBδ) specifically inhibits RelB/p52 dimers—unlike any other IκB—and that p52 represses its own promoter while RelA activates it, revealed pathway-specific inhibition and a negative autoregulatory circuit.

    Evidence Transfection reporter assays, EMSA, and promoter-reporter analysis with RelA versus p52

    PMID:7541912 PMID:7898917

    Open questions at the time
    • Upstream signals controlling this autoregulation not defined
    • In vivo relevance of feedback loop unconfirmed
    • Whether IκBδ activity is regulated post-translationally unknown
  4. 1997 High

    The 2.1 Å crystal structure of the p52 homodimer on DNA revealed structural differences from p50 (rotated insert region, distinct water-mediated contacts) that explain differential κB-site selectivity.

    Evidence X-ray crystallography at 2.1 Å resolution

    PMID:9384586

    Open questions at the time
    • No structure of p52 heterodimers with RelB or p65
    • No structure of full-length p100
    • Structural basis of ankyrin-mediated inhibition unknown
  5. 1999 High

    Mechanistic dissection showed p52 is generated by co-translational proteasomal processing dependent on a glycine-rich region, and that IKKα/β phosphorylate C-terminal serines on p105 to trigger its degradation—identifying the kinase-proteasome axis controlling NF-κB precursor turnover.

    Evidence GRR repositioning mutagenesis, chimeric p100/p105 constructs, in vitro kinase assays with phospho-site mutagenesis in p105, knockout fibroblasts

    PMID:10469655 PMID:10597218

    Open questions at the time
    • E3 ligase mediating p100-specific ubiquitination not yet identified
    • Whether p100 uses identical phospho-sites to p105 unclear
    • Stimulus-specific regulation of co-translational vs. post-translational processing not resolved
  6. 2000 High

    Identification of SCF(β-TrCP) as the E3 ubiquitin ligase that recognizes IKKβ-phosphorylated p105 and ubiquitinates it for proteasomal processing provided the first complete kinase→E3→proteasome pathway for NF-κB precursor destruction.

    Evidence In vitro ubiquitination reconstitution, co-IP of β-TrCP with phospho-p105, dominant-negative β-TrCP blocking processing

    PMID:10835356

    Open questions at the time
    • Whether β-TrCP also mediates p100 processing not established
    • Deubiquitinases counteracting this pathway unknown
    • Quantitative contribution of β-TrCP versus other E3s not addressed
  7. 2002 High

    CD40- and LTβR-induced p100 processing to p52 was shown to require NIK and to proceed via co-translational ubiquitin-proteasome-dependent processing coupled to de novo p100 synthesis, establishing the noncanonical NF-κB pathway as a delayed, translation-dependent signaling cascade.

    Evidence Ubiquitylation assays, proteasome and translation inhibitors, NIK dominant-negative, nuclear fractionation in primary splenic B cells, pulse-chase analysis

    PMID:12374738 PMID:12524526

    Open questions at the time
    • Direct phosphorylation sites on p100 by IKKα not mapped
    • Stoichiometry of co-translational versus post-translational processing unknown
    • Whether all noncanonical stimuli use identical processing mechanisms unclear
  8. 2003 High

    Genetic epistasis in multiple knockout mouse models established that p100 processing to p52-RelB requires NIK and IKKα (but not IKKβ/IKKγ), that TNF-induced p100 accumulation specifically sequesters RelB, and that p52 can switch from transcriptional activation (with Bcl-3) to repression (with HDAC1) at the cyclin D1 promoter, revealing the noncanonical pathway's distinct kinase requirement and the context-dependent transcriptional output of p52.

    Evidence NF-κB2−/−, RelB−/−, NIK−/−, IKKα/β/γ−/− mouse cells, ChIP, co-IP, reporter assays, GSK-3β−/− fibroblasts

    PMID:12505990 PMID:12808109 PMID:12871932

    Open questions at the time
    • Direct phosphorylation events on p100 by IKKα not yet mapped in vivo
    • How Bcl-3/HDAC1 exchange at promoters is regulated temporally unknown
    • In vivo gene targets of the repressive p52/HDAC1 complex not catalogued
  9. 2008 Medium

    Nuclear import of p52 was shown to occur via importin α3/4/5/6 through a monopartite NLS, but within the RelB-p52 heterodimer, import depends exclusively on RelB's bipartite NLS; RelB stability itself requires direct interaction with p100/p52 through all domains, explaining the obligate partnership between RelB and the NFKB2 locus products.

    Evidence In vitro importin binding assays, nuclear translocation assays, stability assays in p100-knockout cells, domain truncation mapping

    PMID:18321863 PMID:18462924

    Open questions at the time
    • Whether importin preference affects target gene selectivity unknown
    • Nuclear export mechanism for p52 dimers not studied
    • Post-translational modifications affecting import not mapped
  10. 2012 High

    Two additional regulatory layers were identified: SCF(Fbw7) as the GSK-3-dependent E3 ligase for p100 destruction (with T cell-specific Fbw7 deletion reducing NF-κB activity), and the noncanonical p52/RelB pathway as essential for CXCL12-dependent cell migration toward HMGB1.

    Evidence Ubiquitination assays, Fbw7-KO and conditional-KO mice, p52-KO cell migration assays with retroviral rescue, CXCR4 neutralization

    PMID:22287708 PMID:22708077

    Open questions at the time
    • Relative contributions of Fbw7 vs. β-TrCP to p100 turnover not quantified
    • Whether Fbw7 and β-TrCP act on distinct p100 pools unknown
    • Full spectrum of noncanonical pathway chemokine targets not mapped
  11. 2013 High

    The discovery that heterozygous C-terminal NFKB2 mutations in CVID patients block p100 phosphorylation and processing, preventing p52 nuclear translocation, established NFKB2 as a Mendelian disease gene and confirmed the noncanonical NF-κB pathway as essential for human antibody-mediated immunity.

    Evidence Whole-exome sequencing, immunoblot and immunofluorescence in patient B cells

    PMID:24140114

    Open questions at the time
    • Precise thymic and B cell developmental stages requiring p52 in humans not defined
    • Genotype-phenotype correlation across different C-terminal mutations incomplete
    • Whether residual processing occurs with missense versus truncating mutations unclear
  12. 2015 High

    Multiple studies revealed target-gene-specific p52 complexes: p52/RelB/HDAC4 represses proapoptotic genes in myeloma; p52 directly activates EZH2 to suppress oncogene-induced senescence in melanoma; p52/RelB with CBP and HDAC1 activates CRH transcription in placenta; and KPC1 was identified as a p105-specific E3 ligase whose overexpression generates excess p50 homodimers with tumor-suppressive properties.

    Evidence ChIP, co-IP, in vitro kinase assays, siRNA knockdown, mouse tumor models, placental tissue analysis, mass spectrometry for KPC1 identification

    PMID:25860612 PMID:26307012 PMID:26364600 PMID:26455434

    Open questions at the time
    • Genome-wide map of p52/RelB versus p52/HDAC targets not available
    • Whether HDAC1 and HDAC4 are used by p52 in a cell-type-specific manner not resolved
    • KPC1 relevance to p100 (rather than p105) processing unknown
  13. 2018 High

    A crystal structure of the p52/ETS1/mutant-TERT-promoter ternary complex revealed that p52 activates the cancer-associated TERT promoter not by binding DNA but by interacting directly with ETS1 to relieve its autoinhibition—demonstrating a non-DNA-binding transcriptional coactivator function for p52.

    Evidence X-ray crystallography of ternary complex, mutagenesis of protein-protein interface, transcriptional reporter assays

    PMID:30093619

    Open questions at the time
    • Prevalence of this non-DNA-binding coactivator mode at other promoters unknown
    • Whether p52 homodimers or heterodimers engage ETS1 in vivo not resolved
    • Structural basis of selectivity for mutant versus wild-type TERT promoter not fully explained
  14. 2019 High

    TRIM14 was shown to recruit the deubiquitinase USP14 to remove K63-linked ubiquitin chains from p100/p52, preventing p62-mediated autophagic degradation and stabilizing the noncanonical NF-κB precursor pool—identifying selective autophagy as a previously unrecognized turnover pathway for p100.

    Evidence Co-IP, in vitro and in vivo deubiquitination assays, TRIM14-KO mice, autophagic flux assays

    PMID:31921549

    Open questions at the time
    • Whether autophagy-mediated p100 degradation is stimulus-dependent not defined
    • Relative contribution of autophagy versus proteasomal degradation to p100 homeostasis unknown
    • Whether USP14 acts on p100 selectively or on other NF-κB subunits as well unclear
  15. 2021 High

    Graded degron mutations in mice demonstrated that autoimmunity from degradation-resistant p100 arises primarily from its IκB function in nonhematopoietic (stromal) cells rather than from p52 insufficiency, with thymic medullary hypoplasia and increased T cell self-reactivity recapitulating human NFKB2-CVID; separately, epithelial p100 was shown to supplement latent RelA dimers and hyperactivate canonical NF-κB in colitis.

    Evidence Mouse genetics with graded degron alleles, radiation chimeras, TCR repertoire sequencing, conditional epithelial manipulation in colitis model

    PMID:33107914 PMID:34155144

    Open questions at the time
    • Whether stromal versus hematopoietic contributions differ across human NFKB2 mutation types not established
    • Mechanism by which p100 supplements latent RelA dimers not fully defined
    • Full autoimmune phenotypic spectrum of C-terminal NFKB2 mutations in mice not catalogued

Open questions

Synthesis pass · forward-looking unresolved questions
  • Outstanding questions include the full genome-wide map of p52-containing complexes and their target genes across cell types, the structural basis for how full-length p100 sequesters RelB, the quantitative contributions of different E3 ligases and autophagic versus proteasomal degradation to p100 homeostasis in different tissues, and the precise genotype-phenotype relationships across the spectrum of human NFKB2 mutations.
  • No structure of full-length p100 or p100-RelB inhibitory complex
  • Genome-wide ChIP-seq for endogenous p52 dimers across primary cell types lacking
  • Quantitative modeling of p100/p52 ratio regulation integrating multiple E3 and DUB inputs not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 3 GO:0140313 molecular sequestering activity 3
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 1
Partners
BCL3ETS1HDAC1HDAC4NFKB1RELARELBTRIM14
Complex memberships
p100/IκBδ-RelB inhibitory complexp52-HDAC1 repressive complexp52-RelB heterodimerp52-p65 heterodimer

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 NFKB2 encodes a 97-kDa precursor protein (p97/p100) that contains an N-terminal Rel-related domain capable of binding κB DNA sites when truncated (producing p50B/p52), and a C-terminal domain with six ankyrin repeats; in vitro-translated truncated proteins bind κB sites, and p50B forms heteromeric complexes with RelB, p65, and p50; transient transfection showed functional cooperation between p50B and RelB or p65 in transactivation. cDNA cloning, in vitro translation, EMSA, co-immunoprecipitation, transient transfection reporter assay Molecular and cellular biology High 1531086
1993 NFKB2/p52 forms a heterodimer with RelA/p65 that binds the HIV κB site with ~6-fold higher affinity than p52 homodimer alone; heterodimeric p52/p65 stimulates in vitro transcription 18-fold; IκBα (MAD-3) inhibits p65, p52/p65, and p50/p65 DNA binding but stimulates p52 or p50 homodimer binding; co-expression of MAD-3 inhibits p52/p65-driven HIV reporter activation in Jurkat cells. Scatchard binding analysis, in vitro transcription assay, EMSA, transient transfection reporter assay Molecular and cellular biology High 8441377
1993 The p100 (p98) precursor forms stable complexes with other Rel/NF-κB family members (p65, c-Rel) via its C-terminal ankyrin repeats and retains them in the cytoplasm; stimulus-responsive processing of p100 generates active NF-κB dimers, providing a second pathway to NF-κB induction distinct from IκBα phosphorylation. Co-immunoprecipitation, cytoplasmic retention assays, stimulus-induced processing assays Genes & development High 8458581
1993 The C-terminal ankyrin repeat domain of p100/p105 inhibits NF-κB DNA binding by masking the nuclear localization signal of the p50 subunit; an acidic region plus six ankyrin repeats are required for high-affinity interaction with Rel proteins; deletion of only three amino acids in the first repeat converts p105 ARD specificity to that of IκBα. Protein interaction assays, deletion mutagenesis, native gel analysis, cross-linking The EMBO journal High 8334994
1995 The C-terminal ankyrin-repeat domain of p100 (IκBδ) functions as a specific inhibitor of RelB/p52 transcriptional activity; in vivo interaction with IκBδ leads to cytoplasmic retention and decreased DNA binding of RelB/p52 complexes; no other known IκB (IκBα, IκBγ, Bcl3) efficiently inhibits the RelB/p52 heterodimer. Transient transfection reporter assay, cytoplasmic retention assay, EMSA Oncogene Medium 7898917
1995 The NFKB2 gene promoters (P1 and P2) contain multiple κB binding sites; RelA transactivates these promoters in a dose-dependent manner, while NF-κB p52 acts as a transcriptional repressor of its own gene, indicating a negative feedback regulatory circuit. Reporter gene transfection (CAT assay), EMSA for κB site binding, RT-PCR for transcript mapping Nucleic acids research Medium 7541912
1997 Crystal structure of human NF-κB p52 homodimer bound to the MHC H-2 κB DNA site at 2.1 Å resolution; p52 structure resembles p50 but shows a rotated insert region that creates a polar cleft presenting potential protein interaction surfaces; water-mediated contacts at the protein-DNA interface distinguish p52 from p50 in binding specificity. X-ray crystallography The EMBO journal High 9384586
1999 p52 is generated from the p100 precursor principally by co-translational processing via the proteasome, dependent on a glycine-rich region (GRR) upstream of the p52 C-terminus; repositioning the GRR alters the site of proteasome cleavage; sequences downstream of the GRR in NFKB2 (but not NFKB1) limit the efficiency of p52 processing, explaining why p52 is produced in smaller amounts than p100 in most cells. In vivo processing assays, chimeric p100/p105 constructs, GRR repositioning mutagenesis Oncogene High 10597218
1999 IKKα and IKKβ physically interact with p105 and inducibly phosphorylate three C-terminal serines; TNFα-induced p105 degradation requires these IKK phospho-acceptor sites; a p105 mutant lacking IKK phosphorylation sites acts as a super-repressor of NF-κB activity. Co-immunoprecipitation, in vitro kinase assay, phospho-site mutagenesis, reporter assay The EMBO journal High 10469655
2000 Following IKKβ-mediated phosphorylation of C-terminal residues 918-934 of p105, the SCF(β-TrCP) ubiquitin ligase is recruited; SCF(β-TrCP) physically associates with phosphorylated p105 and ubiquitinates it in vitro, promoting its processing; dominant-negative β-TrCP inhibits IKK-dependent processing. In vitro ubiquitination reconstitution, co-immunoprecipitation, dominant-negative expression, processing assays The EMBO journal High 10835356
2002 CD40 ligation triggers p100 ubiquitylation and proteasome-mediated processing to p52, which then translocates to the nucleus to form active NF-κB dimers; CD40-mediated p52 production requires functional NIK (NF-κB-inducing kinase) and de novo protein synthesis; in primary splenic B cells, CD40 stimulates delayed nuclear translocation of p52-RelB dimers. Ubiquitylation assay, proteasome inhibitor experiments, NIK dominant-negative transfection, nuclear fractionation, primary B cell stimulation The EMBO journal High 12374738
2003 CD40/LTβR signaling induces p52-RelB dimers via NIK and IKKα (but not IKKβ or IKKγ) through degradation of p100; TNF activates only RelA via all three IKK subunits; TNF also increases p100 levels, which specifically inhibits RelB DNA binding through the C-terminus of p100; p52-RelB heterodimers are required for Peyer's patch development. Genetic mouse models (NF-κB2-/-, RelB-/-, NIK-/-, IKKα/β/γ-/- cells), EMSA, nuclear fractionation, EMSA with IKK siRNAs The EMBO journal High 12505990
2003 p52 induces transcriptional repression of cyclin D1 by associating with HDAC1 (replacing Bcl-3 coactivator complexes); p53 induction causes decreased Bcl-3 expression and increased p52/HDAC1 complex formation at the cyclin D1 promoter; p52/Bcl-3 activates while p52/HDAC1 represses cyclin D1 transcription. Co-immunoprecipitation, reporter assays, chromatin immunoprecipitation, knockdown/overexpression Molecular and cellular biology High 12808109
2003 LTβ receptor agonists and LPS induce p100 processing to p52 via a co-translational mechanism; p100 is constitutively and inducibly polyubiquitinated; p52 generation by these stimuli is coupled to ongoing p100 translation (ribosome-associated processing), is delayed relative to canonical NF-κB, and requires de novo protein synthesis. Ubiquitination assay, inhibitor studies (proteasome, translation), EMSA, pulse-chase analysis EMBO reports High 12524526
2003 GSK-3β forms an in vivo complex with p105 and phosphorylates it at Ser-903 and Ser-907 in vitro; GSK-3β stabilizes p105 under resting conditions but primes it for degradation in response to TNFα; constitutive processing of p105 to p50 is elevated in GSK-3β-/- fibroblasts. Co-immunoprecipitation, in vitro kinase assay with site-specific mutagenesis, GSK-3β-/- fibroblasts, processing assays The Journal of biological chemistry High 12871932
2006 IKKα regulates G1-to-S phase progression by controlling the transcription of the skp2 gene through a p52/RelB-containing NF-κB complex; IKKα knockdown elevates p27(Kip1) by downregulating skp2; the mechanism involves IKKα-dependent composition changes of the RelB/p52 complex at the skp2 promoter. IKKα-specific siRNA knockdown, ChIP, reporter assays, protein level analysis in pancreatic cancer cells The EMBO journal Medium 16902410
2008 p52 is imported into the nucleus via direct binding to importin α3, α4, α5, and α6 through a monopartite NLS; when p52 forms a heterodimer with RelB, nuclear import is mediated exclusively by the bipartite NLS of RelB; when p52 forms a heterodimer with p65, the NLS of p52 mediates nuclear import of the dimer. In vitro binding assay of importin α isoforms with in vitro-translated NF-κB proteins, nuclear translocation assays Cellular signalling Medium 18462924
2008 RelB stabilizes itself by directly interacting with p100/p52; RelB protein levels are significantly reduced in the absence of p100; all domains of both RelB and p100 are engaged in their complex, whereas only the N-terminal RHD of p100/p52 (not p105) interacts with RelB; the transcriptional activation domain of RelB directly contacts the processing region of p100, explaining why RelB preferentially partners with p52. Co-immunoprecipitation, protein stability assays in p100/p105 knockout cells, domain mapping with truncation constructs The Journal of biological chemistry High 18321863
2010 Processing of NF-κB2 p100 to p52 is critical for RANKL-induced osteoclast differentiation; NIK-mediated p100 processing is required for NFATc1 induction by RANKL; overexpression of constitutively active IKKα or p52 restores osteoclastogenesis in NIK-inactive (aly/aly) bone marrow cells; the ratio of p52 to p100 correlates with osteoclast numbers. Aly/aly mouse model (inactive NIK), RANKL stimulation, overexpression rescue experiments, transfection of p100 variants Journal of bone and mineral research High 19874202
2010 NF-κB2/p52 activates the androgen receptor (AR) in a ligand-independent manner by interacting with its NH2-terminal domain; p52 enhances nuclear translocation and activation of AR and recruits the coactivator p300 to AR-dependent gene promoters; knockdown of endogenous p52 abrogates AR constitutive activation in castration-resistant prostate cancer cells. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, RNAi knockdown, AR-responsive gene expression analysis Cancer research High 20388792
2012 The IKKα-dependent p52/RelB noncanonical pathway is essential for sustaining CXCL12 production required for cell migration toward HMGB1; p52 KO cells show a migration defect rescuable by exogenous CXCL12 or by retroviral CXCL12 expression; CXCR4 (CXCL12 receptor) neutralization blocks HMGB1 chemotaxis. IKKα KO and p52 KO mouse cells, cytokine neutralization, receptor antagonism, retroviral rescue, migration assays Journal of immunology High 22287708
2012 SCF(Fbw7) is the E3 ubiquitin ligase that mediates ubiquitination and destruction of NF-κB2/p100 in a GSK3-dependent manner; Fbw7-/- cells show elevated p100 and reduced NF-κB signaling; reintroduction of wild-type but not tumor-derived mutant Fbw7 rescues NF-κB activity; T cell-specific Fbw7 deletion leads to reduced NF-κB activity and perturbed T cell differentiation. Ubiquitination assays, Fbw7 KO cells, rescue with wild-type vs. mutant Fbw7, T cell-specific conditional KO Cell reports High 22708077
2013 Germline heterozygous frameshift and nonsense mutations in NFKB2 affecting the C-terminus of p100 impair phosphorylation and proteasomal processing of p100, blocking p52 nuclear translocation; this establishes the noncanonical NF-κB pathway as a genetic etiology for CVID. Whole exome sequencing, immunoblot of patient B cells, immunofluorescence microscopy American journal of human genetics High 24140114
2015 KPC1 is the E3 ubiquitin ligase that binds the ankyrin repeat domain of p105, ubiquitinates it, and mediates its processing to p50 under both basal and signaling conditions; KPC1 overexpression restricts tumor growth, possibly through excessive p50 generation that forms p50-p50 homodimers replacing tumorigenic p50-p65. Mass spectrometry identification of KPC1-p105 interaction, ubiquitination assays, KPC1 overexpression in tumor models Cell High 25860612
2015 An HDAC4-RelB-p52 complex maintains repressive chromatin around proapoptotic genes Bim and BMF in multiple myeloma cells; ERK1 phosphorylates RelB and phospho-RelB is largely nuclear; disruption of RelB-HDAC4 interaction blocks MM growth; RelB-p52 also represses BMF translation by regulating miR-221. Co-immunoprecipitation, ChIP, in vitro kinase assay identifying ERK1 as RelB kinase, dominant-negative peptide, knockdown Nature communications High 26455434
2015 NF-κB2/p52 directly transcriptionally activates EZH2 expression in melanoma cells; inhibition of noncanonical NF-κB by targeting p52 or NIK decreases EZH2 and restores the senescence program; overexpression of p52 in normal melanocytes prevents oncogene-induced senescence. ChIP, reporter assays, siRNA knockdown of p52/NIK, p52 overexpression, mouse tumor models Oncogene Medium 26364600
2015 Glucocorticoid/RelB/p52-mediated noncanonical NF-κB signaling induces CRH expression in full-term placenta through a transcription complex containing RelB/p52, CBP, and HDAC1; CBP and HDAC1 bind at the CRH promoter in a complex with RelB/p52 in a mutually dependent manner; knockdown of any one factor prevents binding of the others and abrogates dexamethasone-induced CRH expression. ChIP, co-immunoprecipitation, siRNA knockdown, histone acetylation analysis Science signaling High 26307012
2017 Nonsense NFKB2 mutations (E418X, R635X) produce truncated p52-like proteins that constitutively localize to the nucleus and activate both canonical and noncanonical NF-κB pathways; an S866R missense mutation disrupts a critical C-terminal phosphorylation site blocking p100 processing and p52 nuclear translocation. Immunoblotting, immunohistochemistry, luciferase reporter assays, flow cytometry of patient PBMCs, HEK293T transfection Blood High 28778864
2018 Crystal structure of a ternary p52/ETS1/-146C>T TERT promoter complex shows that p52 activates the mutant TERT promoter without binding DNA; instead, p52 interacts directly with ETS1 to form a heterotetramer that counteracts autoinhibition of ETS1; native flanking ETS motifs are required for sustained activation. X-ray crystallography of ternary complex, mutagenesis, transcriptional reporter assays Nature communications High 30093619
2019 TRIM14 promotes noncanonical NF-κB activation by recruiting deubiquitinase USP14 to cleave K63-linked ubiquitin chains from p100/p52, thereby preventing p62-mediated autophagic degradation of p100/p52 and increasing its abundance; TRIM14 deficiency in mice impairs noncanonical NF-κB-mediated inflammatory responses. Co-immunoprecipitation, in vitro and in vivo deubiquitination assays, TRIM14 KO mice, autophagic flux assays Advanced science High 31921549
2021 Cell-autonomous Nfkb2/p100 signaling in intestinal epithelial cells supplements latent NF-κB dimers (particularly latent RelA complexes) to the canonical NF-κB module, thereby hyperactivating RelA-driven proinflammatory gene responses in the inflamed colon and exacerbating colitis pathology. Mouse model of experimental colitis, epithelial-specific genetic manipulation, NF-κB pathway analysis, gene expression Proceedings of the National Academy of Sciences Medium 34155144
2021 Severe p100-degradation resistance (due to mutations in the p100 degron) causes thymic medullary hypoplasia and autoimmune disease in mice; autoimmunity arises largely from defects in nonhematopoietic cells caused by the IκB function of degradation-resistant p100, not from p52 insufficiency; the T cell receptor repertoire shows increased self-reactivity in both affected mice and humans with NFKB2 C-terminal mutations. Mouse genetics with graded degron mutations, radiation chimeras, TCR repertoire sequencing, thymic histology The Journal of experimental medicine High 33107914

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 CD40 regulates the processing of NF-kappaB2 p100 to p52. The EMBO journal 350 12374738
1991 Generation of p50 subunit of NF-kappa B by processing of p105 through an ATP-dependent pathway. Nature 294 1956402
1993 p105 and p98 precursor proteins play an active role in NF-kappa B-mediated signal transduction. Genes & development 284 8458581
1992 A novel mitogen-inducible gene product related to p50/p105-NF-kappa B participates in transactivation through a kappa B site. Molecular and cellular biology 283 1531086
2012 Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing. PLoS genetics 278 22615581
2007 Distinct roles for the XPB/p52 and XPD/p44 subcomplexes of TFIIH in damaged DNA opening during nucleotide excision repair. Molecular cell 227 17466626
2003 p53 represses cyclin D1 transcription through down regulation of Bcl-3 and inducing increased association of the p52 NF-kappaB subunit with histone deacetylase 1. Molecular and cellular biology 214 12808109
2013 Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency. American journal of human genetics 196 24140114
1997 The retinoblastoma gene family pRb/p105, p107, pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas. Nature medicine 179 9256285
1999 NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of Bcl-3-p50 complexes. The EMBO journal 174 10469655
2003 RelB is required for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF. The EMBO journal 165 12505990
2000 SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase. The EMBO journal 156 10835356
2003 Glycogen synthase kinase-3 beta regulates NF-kappa B1/p105 stability. The Journal of biological chemistry 139 12871932
2006 Proteasome-mediated degradation of IkappaBalpha and processing of p105 in Crohn disease and ulcerative colitis. The Journal of clinical investigation 133 17124531
1997 Induction of the transcription factor Sp1 during human cytomegalovirus infection mediates upregulation of the p65 and p105/p50 NF-kappaB promoters. Journal of virology 133 9151857
1996 Effects on NF-kappa B1/p105 processing of the interaction between the HTLV-1 transactivator Tax and the proteasome. Nature 129 8692272
1993 Dimerization of NF-KB2 with RelA(p65) regulates DNA binding, transcriptional activation, and inhibition by an I kappa B-alpha (MAD-3). Molecular and cellular biology 128 8441377
2007 Plasmodium yoelii sporozoites with simultaneous deletion of P52 and P36 are completely attenuated and confer sterile immunity against infection. Infection and immunity 127 17517871
1997 Structure of the human NF-kappaB p52 homodimer-DNA complex at 2.1 A resolution. The EMBO journal 119 9384586
2019 Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2. Frontiers in immunology 117 30941118
1993 Structural alterations of the NF-kappa B transcription factor lyt-10 in lymphoid malignancies. Oncogene 117 8378093
2003 NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity. Molecular and cellular biology 107 12832462
2003 Lymphotoxin and lipopolysaccharide induce NF-kappaB-p52 generation by a co-translational mechanism. EMBO reports 104 12524526
2015 KPC1-mediated ubiquitination and proteasomal processing of NF-κB1 p105 to p50 restricts tumor growth. Cell 93 25860612
1999 The generation of nfkb2 p52: mechanism and efficiency. Oncogene 91 10597218
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