Affinage

NFKBIA

NF-kappa-B inhibitor alpha · UniProt P25963

Length
317 aa
Mass
35.6 kDa
Annotated
2026-06-10
100 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IκBα (NFKBIA) is the principal cytoplasmic inhibitor of NF-κB, governing the inducibility and dynamics of NF-κB-dependent transcription in inflammation, development, and tumorigenesis (PMID:9865693, PMID:8631829). Its ankyrin repeat domain clamps the C-terminal Rel homology regions of the p50/p65 heterodimer, masking the p65 nuclear localization signal and occluding the DNA-binding cleft so the dimer is retained in an inactive cytoplasmic state (PMID:9865693); binding is governed by coupled folding of ankyrin repeats 5–6, such that incomplete folding weakens NF-κB capture and compromises inhibition (PMID:18511071). Upon inflammatory signaling, IκBα is phosphorylated at S32/S36 — by IKK and additionally by CKII and GRK6 — which licenses recognition by the SCF^β-TrCP E3 ligase, K48-linked polyubiquitination, and proteasomal degradation, an obligatory order in which phosphorylation precedes ubiquitination (PMID:8631829, PMID:9859996, PMID:10398585, PMID:25881508); the p97-UFD1L-NPL4 ATPase complex acts post-ubiquitinationally to drive efficient proteolysis (PMID:24248593). IκBα turnover is dual: free IκBα is degraded rapidly through a ubiquitin-independent, PEST-dependent proteasomal route, whereas NF-κB-bound IκBα masks the PEST domain and is degraded slowly via the phosphorylation/ubiquitination route (PMID:18401342). Multiple non-canonical routes also dismantle the inhibitor — CK2- or HK2(T291)-primed calpain cleavage, an IKK-independent genotoxic-stress pathway, and tyrosine-181 nitration that dissociates intact IκBα from NF-κB without proteolysis (PMID:11673497, PMID:36007522, PMID:14585967, PMID:17910475). Beyond cytoplasmic sequestration, free IκBα is actively imported into the nucleus via its ankyrin repeats and importin α/β, where it strips NF-κB from DNA through long-range allosteric twisting of the heterodimer and exports it via CRM1 with 14-3-3 assistance, making nuclear transport kinetics a determinant of post-induction repression and re-activation (PMID:10037782, PMID:28249778, PMID:16931600, PMID:26311312). NFKBIA is itself an NF-κB-inducible negative-feedback gene whose output is tuned epigenetically and transcriptionally, including KDM5B-mediated erasure of H3K4me3 at the promoter to permit full NF-κB activation (PMID:36914768). Phosphorylated IκBα additionally associates with nucleosomes via histones H2A/H4 in an H4-acetylation-dependent manner, contributing to intestinal epithelial differentiation (PMID:34224210).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    Established the causal order of the canonical degradation switch — that signal-induced phosphorylation of IκBα is a prerequisite for its inducible ubiquitination and proteasomal destruction.

    Evidence TNFα stimulation with proteasome inhibition, anti-ubiquitin IP, and an S32A/S36A non-phosphorylatable mutant

    PMID:8631829

    Open questions at the time
    • Did not identify the E3 ligase that reads the phosphodegron
    • Did not resolve the kinase responsible in vivo
  2. 1998 High

    Defined the structural basis of NF-κB inhibition, showing how ankyrin repeats mask the p65 NLS and occlude the DNA-binding cleft.

    Evidence 2.7 Å X-ray crystal structure of the IκBα ankyrin domain bound to a truncated p50/p65 heterodimer

    PMID:9865693

    Open questions at the time
    • Truncated NF-κB lacked full-length context
    • Did not capture the molecular-stripping transition state
  3. 1998 High

    Identified β-TrCP as the substrate-recognition receptor that reads phospho-IκBα, completing the canonical phospho-ubiquitin module.

    Evidence Immunoaffinity purification with MS identification, in vitro reconstituted ubiquitination, and dominant-negative F-box mutant in vivo

    PMID:9859996

    Open questions at the time
    • Did not address post-ubiquitination handoff to the proteasome
    • Did not address basal versus induced turnover
  4. 1999 High

    Showed that free IκBα is not merely a static cytoplasmic anchor but is actively imported into the nucleus, establishing nuclear shuttling as part of its regulatory repertoire.

    Evidence Import assays in digitonin-permeabilized cells with importin α/β/Ran dependence and ankyrin-repeat competition

    PMID:10037782

    Open questions at the time
    • Identity of the ankyrin-recognizing import factor not resolved
    • Functional consequence of nuclear IκBα not yet shown
  5. 1999 Medium

    Demonstrated that S32/S36 phosphorylation is not exclusive to IKK, with CKII directly modifying the same sites, broadening the kinase input.

    Evidence In vitro kinase assay with purified CKII and co-IP of endogenous CKII-IκBα

    PMID:10398585

    Open questions at the time
    • Physiological signal triggering CKII phosphorylation unclear
    • Relative contribution versus IKK in vivo not quantified
  6. 2001 High

    Uncovered a non-canonical, calpain-dependent destruction route primed by CK2 phosphorylation of PEST-domain residues, distinct from the proteasomal pathway.

    Evidence In vitro CK2 phosphorylation/calpain degradation with an S283A/T291A/T299A mutant in IgM+ B cells

    PMID:11673497

    Open questions at the time
    • Physiological signal coupling CK2 to calpain not defined
    • Generality beyond B cells unaddressed
  7. 2003 High

    Showed NF-κB can be activated through IKK-independent, phosphorylation- and PEST-independent IκBα degradation under genotoxic stress, revealing pathway redundancy.

    Evidence IKK1/2-double-knockout MEFs with doxorubicin, phospho-mutant IκBα, PI3K and proteasome inhibitors, chromatin reporter

    PMID:14585967

    Open questions at the time
    • E3 ligase for this route not identified here
    • Degron recognized in absence of S32/S36 unknown
  8. 2006 High

    Identified 14-3-3 as an obligate partner for CRM1-dependent nuclear export of p65-IκBα complexes, linking export machinery to NF-κB termination.

    Evidence Reciprocal co-IP, domain mapping, dominant-negative 14-3-3, and ChIP

    PMID:16931600

    Open questions at the time
    • Whether 14-3-3 binding is phospho-regulated not resolved
    • Stoichiometry of the export complex undetermined
  9. 2008 High

    Resolved two kinetically distinct degradation pathways and showed NF-κB binding protects IκBα by masking its PEST domain, explaining how free versus bound pools are differentially controlled.

    Evidence Biochemical fractionation, proteasome and ubiquitination assays, PEST-domain mutants, protein half-life measurements

    PMID:18401342

    Open questions at the time
    • Proteasomal recognition of free PEST not structurally defined
    • In vivo balance of the two pools not quantified
  10. 2008 High

    Demonstrated that coupled folding-and-binding of ankyrin repeats 5–6 is functionally required, linking IκBα conformational dynamics to the strength of NF-κB inhibition and to its own turnover rate.

    Evidence Stabilizing AR5-6 mutagenesis with SPR, ITC, co-IP, and pulse-chase half-life assays

    PMID:18511071

    Open questions at the time
    • In vivo signaling consequences only inferred from cell assays
    • Folding intermediates not structurally characterized
  11. 2017 Medium

    Provided the biophysical mechanism of molecular stripping, showing IκBα allosterically destabilizes the DNA-bound state to actively remove NF-κB from DNA.

    Evidence HDX-MS coupled with coarse-grained molecular dynamics simulations

    PMID:28249778

    Open questions at the time
    • No mutagenesis confirmation of the specific repulsive contacts
    • Kinetics in living cells not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full set of E3 ligases, deubiquitinases, kinases, and metabolic enzymes reported to converge on IκBα has not been reconciled into a quantitative model of when each route dominates in a given cell type or stimulus.
  • Many regulators (e.g. TRIM22, N4BP3, FBXO32, USP14/USP39, HK2, FBP1) rest on single-lab co-IP/functional studies without in vitro reconstitution
  • Cell-type and stimulus specificity of canonical versus non-canonical degradation unresolved
  • Interplay between nuclear stripping, chromatin binding, and feedback transcription not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 3 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0000228 nuclear chromosome 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3
Partners
BTRCG3BP2NFKB1RELARPS3TRIM67VCP (P97)YWHA (14-3-3)
Complex memberships
NF-κB/IκBα (p50/p65) complexSCF^β-TrCP ubiquitin ligase

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Crystal structure of the IκBα ankyrin repeat domain bound to a truncated NF-κB (p50/p65) heterodimer at 2.7 Å resolution reveals that six IκBα ankyrin repeats contact the C-terminal Rel homology regions of NF-κB in discontinuous patches; the first two repeats cover an alpha-helically ordered segment containing the p65 NLS, and the sixth repeat position indicates that full-length IκBα occludes the NF-κB DNA-binding cleft. X-ray crystallography Cell High 9865693
1998 The F-box/WD-domain protein E3RSIκBα (β-TrCP) was identified as the receptor component of the pIκBα-ubiquitin ligase (pIκBα-E3) that specifically recognizes phosphorylated IκBα and promotes its in vitro ubiquitination in the presence of E1 and UBC5C; an F-box-deletion dominant-negative mutant blocked pIκBα degradation and NF-κB activation in vivo. Immunoaffinity purification from HeLa cells, nanoelectrospray mass spectrometry, in vitro ubiquitination assay, dominant-negative in vivo experiments Nature High 9859996
1996 Signal-induced NF-κB activation requires phosphorylation-dependent ubiquitination of IκBα: TNFα stimulation causes rapid accumulation of multi-ubiquitinated IκBα that dissociates from NF-κB when proteasomal degradation is blocked; an S32A/S36A IκBα mutant that cannot be phosphorylated also fails to undergo inducible ubiquitination, placing phosphorylation upstream of ubiquitination and proteasomal degradation. Proteasome inhibitor treatment, recombinant ubiquitin carboxyl-terminal hydrolase de-ubiquitination assay, anti-ubiquitin immunoprecipitation, epitope-tagged ubiquitin Western blot, site-directed mutagenesis The Journal of Biological Chemistry High 8631829
2008 Two distinct degradation pathways control IκBα levels: free IκBα is degraded rapidly in a ubiquitin-independent, PEST-domain-dependent manner by the proteasome, whereas NF-κB-bound IκBα is protected from this pathway and requires IKK phosphorylation and ubiquitination for slower basal degradation. NF-κB binding masks the PEST domain from proteasomal recognition. Biochemical fractionation, proteasome inhibitor assays, ubiquitination assays, PEST-domain deletion/mutation analysis, quantitative protein half-life measurements The EMBO Journal High 18401342
1999 IκBα (when not bound to NF-κB) is constitutively and actively imported into the nucleus via an energy-dependent, importin α/β- and Ran-dependent mechanism that requires the ankyrin repeats of IκBα and additional factor(s) recognizing those repeats ('piggy-back' mechanism); binding to NF-κB retains IκBα in the cytoplasm. Nuclear import assays using digitonin-permeabilized cells, energy-depletion experiments, ankyrin-repeat competition/depletion from cell extracts, subcellular fractionation The Journal of Biological Chemistry High 10037782
2000 The cytoplasmic protein G3BP2 (RasGAP SH3-binding protein 2) interacts with both free IκBα and IκBα/NF-κB complexes via the N-terminal domain of IκBα, and its overexpression promotes cytoplasmic retention of IκBα, adding cytoplasmic anchoring to nuclear import/export as a mechanism controlling IκBα localization. Co-immunoprecipitation, pulldown, overexpression localization experiments, domain-mapping The Journal of Biological Chemistry Medium 10969074
2001 CK2 phosphorylation of serine/threonine residues in the PEST domain of IκBα (S283, T291, T299) promotes calpain-mediated degradation of IκBα, as demonstrated by in vitro CK2 phosphorylation/calpain degradation assays; a 3CIκBα mutant (S283A/T291A/T299A) resists calpain-mediated degradation, identifying a non-canonical degradation route active in IgM+ B cells. In vitro phosphorylation/degradation assay, site-directed mutagenesis (S283A/T291A/T299A), calpain inhibitor experiments, CK2 inhibitor (apigenin) treatment Journal of Immunology High 11673497
2003 An IKK-independent IκBα degradation pathway exists: in IKK1/2−/− MEFs, doxorubicin induces IκBα degradation that does not require S32/S36 phosphorylation or the PEST domain, is partially blocked by PI3-kinase inhibitor LY294002, and is proteasome-dependent; the released NF-κB can activate chromatin-based reporter genes. IKK1/2 double-knockout MEFs, phospho-mutant IκBα, PI3-kinase inhibitor, proteasome inhibitor, NF-κB chromatin reporter assay Molecular and Cellular Biology High 14585967
2006 14-3-3 proteins physically interact with IκBα (residues 60–65) and with p65, and are required for efficient CRM1-dependent nuclear export of p65-IκBα complexes; mutations in the 14-3-3 binding domains cause nuclear accumulation of both proteins, and dominant-negative 14-3-3 leads to constitutive chromatin association of p65 with loss of TNFα responsiveness. Co-immunoprecipitation, domain-mapping mutagenesis, dominant-negative overexpression, ChIP, subcellular fractionation, fluorescence microscopy Journal of Cell Science High 16931600
2007 Ionizing radiation activates NF-κB by a mechanism in which constitutive NO synthase activation leads to nitration of IκBα tyrosine 181, causing dissociation of intact IκBα from NF-κB without requiring IKK-dependent phosphorylation or proteolytic degradation of IκBα; crystallographic analysis shows Y181 is involved in noncovalent contacts with NF-κB p50. Cell-based NF-κB assays, NO synthase inhibitors, mutational analysis of Y181, hydropathic analysis of crystal structure contacts Biochemistry Medium 17910475
2008 Stabilizing mutations in IκBα ankyrin repeats 5–6 cause them to pre-fold cooperatively; pre-folded IκBα is degraded more slowly by the ubiquitin-independent proteasome pathway, binds NF-κB more weakly (shown by SPR, ITC, and immunoprecipitation), and results in incomplete NF-κB inhibition at rest and reduced nuclear NF-κB upon stimulation, demonstrating that coupled folding-and-binding of IκBα is critical for NF-κB control. Stabilizing mutagenesis of AR5–6, surface plasmon resonance, isothermal titration calorimetry, co-immunoprecipitation, pulse-chase protein half-life assay in cells Journal of Molecular Biology High 18511071
2012 TNFα stimulation induces formation of heterologous SUMO-2/3-ubiquitin chains on IκBα; deficient SUMOylation (Ubc9 silencing) delays TNFα-mediated IκBα proteolysis and NF-κB-dependent transcription; hybrid SUMO-2/3-ubiquitin chains promote more efficient degradation of IκBα by the 26S proteasome in vitro compared with either modification alone. In vitro proteasome degradation assay with hybrid chains, TUBE-based ubiquitin-trap capture, Ubc9 siRNA knockdown, TNFα stimulation assays PloS One Medium 23284737
2013 The p97-UFD1L-NPL4 protein complex mediates the post-ubiquitinational step of IκBα proteolysis after TNFα or IL-1β stimulation: p97 associates with the SCFβ-TRCP ubiquitin ligase, and UFD1L's polyubiquitin-binding domain binds polyubiquitinated IκBα; ATPase activity of p97 is essential for efficient IκBα degradation and NF-κB activation. Co-immunoprecipitation, ATPase-dead p97 mutant, siRNA knockdown, TNFα/IL-1β stimulation assays Molecular and Cellular Biology Medium 24248593
2001 IκBα can sequester ribosomal protein S3 (RPS3) in the cytoplasm: in resting HEK293 cells, RPS3 co-precipitates with IκBα; in vitro reconstitution shows strong direct IκBα–RPS3 binding but weak RPS3–p65 binding; IκBα facilitates assembly of p65 and RPS3 into a trimeric complex, suggesting equimolar co-release of RPS3 and p65 upon stimulation. Co-immunoprecipitation, in vitro binding (pulldown), reconstitution of trimeric complex FEBS Letters Medium 24457201
2017 IκBα binding to NF-κB induces long-range allosteric conformational changes: amide H/D exchange shows that IκBα binding to the dimerization domains globally stabilizes the DNA-binding domains, whereas DNA binding increases exchange in the NLS region, consistent with a 'molecular stripping' mechanism whereby IκBα electrostatically repels DNA and twists the NF-κB heterodimer. Hydrogen/deuterium exchange mass spectrometry (HDX-MS), coarse-grained molecular dynamics simulations Journal of Molecular Biology Medium 28249778
2021 Transcriptional silencing of NFKBIA (encoding IκBα) by the histone demethylase KDM5B mediates constitutive NF-κB activation in senescent cells: during the second phase of DNA-damage-induced NF-κB activation, altered GSK3β-dependent phosphorylation of p65/RelA leads to NFKBIA transcriptional repression and IKK-independent, proteasome-independent NF-κB activity. RNA-seq, ChIP-seq, GSK3β inhibitor treatment, IKK inhibitor treatment, proteasome inhibitor treatment, siRNA knockdown The EMBO Journal Medium 33459422
2023 The histone demethylase KDM5B is recruited to the Nfkbia promoter in activated macrophages and erases H3K4me3 marks, reducing chromatin accessibility and suppressing IκBα expression to permit full NF-κB activation; KDM5B deficiency or inhibition protects mice from inflammatory disease models. Genome-wide ChIP-seq (KDM5B binding peaks), ATAC-seq (chromatin accessibility), KDM5B KO mice, inhibitor treatment, collagen-induced arthritis and endotoxin shock models Cell Death and Differentiation High 36914768
2022 Hexokinase 2 (HK2) acts as a protein kinase that phosphorylates IκBα at T291 upon high-glucose stimulation; this phosphorylation increases IκBα interaction with μ-calpain, leading to μ-calpain-mediated IκBα degradation, NF-κB activation, and PD-L1 upregulation; expression of IκBα T291A blocked these effects. Co-immunoprecipitation, in vitro kinase assay, T291A phospho-mutant, calpain inhibitors, shRNA knockdown, orthotopic tumor models Cell Metabolism High 36007522
2020 TRIM22 E3 ubiquitin ligase directly binds IκBα (by co-immunoprecipitation), promotes K48-linked ubiquitination of IκBα accelerating its degradation, and also forms a complex with IKKγ to promote K63-linked ubiquitination leading to IKKα/β phosphorylation; RING-domain or active-site TRIM22 mutants fail to promote GBM cell proliferation. Co-immunoprecipitation, luciferase reporter assay, RING-domain deletion and C15/18A active-site mutagenesis, CRISPR/Cas9 knockout, orthotopic xenograft Cell Death and Differentiation Medium 32814880
2020 HDAC4 acts as a SUMO E3 ligase (via its Cys292) that directly sumoylates IκBα; IκBα sumoylation at Lys21 competes with K48-linked polyubiquitination at the same residue, thereby preventing IκBα degradation and inhibiting NF-κB activation; cytoplasmic localization of HDAC4 is required for this activity. SUMO E3 ligase assay, co-immunoprecipitation, HDAC4 Cys292 mutagenesis, Lys21 IκBα mutation, subcellular fractionation Journal of Molecular Cell Biology Medium 32770227
2023 Gluconeogenic enzyme FBP1 directly dephosphorylates IκBα at S32/S36 upon TNFα stimulation: identified by phosphoproteomic analysis, confirmed by molecular docking and MD simulations showing catalytic mechanism analogous to F-1,6-BP dephosphorylation; FBP1-IκBα interaction established by co-immunoprecipitation; FBP1-dependent IκBα dephosphorylation inhibits NF-κB and suppresses colorectal tumorigenesis. High-throughput screening with molecular docking/MD simulations, phosphoproteomic analysis, co-immunoprecipitation, FBP1 overexpression/knockdown, colorectal tumor xenograft models Cell Research Medium 36646759
2015 GRK6 directly phosphorylates IκBα at Ser32/Ser36 in vitro and in cells; TNFα induces a conformational change in GRK6 (detected by BRET probe), and GRK6 kinase activity promotes NF-κB signaling and inflammatory gene transcription after TNFα stimulation; GRK6 knockout in macrophages attenuates this response. In vitro kinase assay, GRK6 knockout macrophages, BRET conformational sensor, TNFα stimulation assays Biochemical and Biophysical Research Communications Medium 25881508
2013 BCL10, MALT1, and IKK inducibly associate with IκBα in a complex physically distinct from the early CK1α-CBM signalosome during TCR signaling; siRNA knockdown of CARMA1, CK1α, or BCL10 prevents assembly of this IκBα-containing complex and reduces NF-κB activation; IκBα knockdown alters BCL10-MALT1 ubiquitylation, suggesting IκBα participates in MALT1 recycling. Co-immunoprecipitation, siRNA knockdown (CARMA1, CK1α, BCL10, IκBα), T-cell receptor stimulation assays Journal of Cell Science Medium 20551178
2018 Bmi1 polycomb protein associates with the SCF ubiquitin complex via its N-terminus and, following IKKα/β-dependent phosphorylation, promotes IκBα ubiquitination in the cytoplasm; Bmi1 deficiency inhibits NF-κB-mediated gene expression and an NF-κB-dependent arthritis model in vivo. Co-immunoprecipitation, Bmi1 N-terminal deletion mutants, IKK inhibitor, Bmi1 knockout, collagen-induced arthritis model Journal of Immunology Medium 30209188
2018 USP14 deubiquitinating enzyme interacts with IκBα and promotes its deubiquitination and degradation (paradoxically exacerbating NF-κB activation), thereby creating a feed-forward loop that aggravates IL-1β-induced chondrocyte dedifferentiation; USP14 upregulation itself depends on NF-κB pathway activity. Co-immunoprecipitation, USP14 overexpression/knockdown, IKK-β inhibitor (ACHP), Western blot, chondrocyte differentiation assays Life Sciences Low 30550885
2019 Hypoxia (1% O2) inhibits RANKL-dependent phosphorylation of IκBα in osteoclast precursors, thereby suppressing NFATc1 expression and osteoclast differentiation and bone resorption. RAW264.7 cells and bone marrow monocytes in hypoxic chamber, RANKL stimulation, Western blot for p-IκBα and p-JNK, TRAP staining, bone resorption assay Inflammation Research Low 30604211
2019 Hypoxia induces rapid, transient accumulation of both RelA and IκBα within mitochondria in a ROS- and STAT3-dependent manner; STAT3 inhibition blocks mitochondrial RelA and IκBα localization; p50 is instead found in the ER and RelA alone is present in the mitoplast. Subcellular fractionation (mitochondria isolation), mitoplast fractionation, hypoxia treatment, ROS scavenger, STAT3 inhibitor, Western blot Bioscience Reports Medium 31484794
2021 Phosphorylated IκBα (pS-IκBα) binds to nucleosomes via histones H2A and H4; serine 32/36 phosphorylation of IκBα favors its binding to nucleosomes; this association depends on acetylation of specific H4 lysine residues; proteolytic cleavage of the H4 N-terminal tail by trypsin/chymotrypsin reduces pIκBα chromatin binding; dynamic chromatin binding of IκBα is required for intestinal cell differentiation. Chromatin immunoprecipitation, co-immunoprecipitation with nucleosome components, phospho-mutant IκBα, H4 acetylation analysis, trypsin/chymotrypsin inhibitor treatment, IκBα deletion in intestinal organoids EMBO Reports Medium 34224210
2023 USP39 deubiquitinating enzyme interacts with IκBα and removes K48-linked polyubiquitin chains, stabilizing basal IκBα and suppressing NF-κB-mediated inflammatory responses; USP39 knockdown/knockout in macrophages increases pro-inflammatory cytokine secretion; USP39-defective mice are more sensitive to LPS-induced sepsis. Co-immunoprecipitation, USP39 siRNA/CRISPR knockout, K48-linked ubiquitination assay, LPS stimulation, in vivo sepsis model Journal of Immunology Medium 36651806
2015 Nuclear import rate, nuclear export rate of free IκBα, and the half-life of free IκBα are identified as critical determinants of post-induction NF-κB repression and the potential for NF-κB re-activation; NF-κB-inducible expression of IκBα alone is not sufficient for effective negative feedback—the biophysical properties of IκBα nuclear transport are also required. Computational modeling of NF-κB signaling, single-cell live imaging, biochemical half-life measurements, nuclear import/export perturbation experiments Journal of the Royal Society Interface Medium 26311312
2001 IκBα differentially regulates NF-κB subunit nuclear localization in a subunit composition-dependent manner: IκBα binding attenuates nuclear import potential of p65 and c-Rel homodimers but not p50-associated heterodimers, leading to a greater propensity of heterodimers to reside in the nucleus; c-Rel-IκBα complexes in mature B cells result in nuclear c-Rel accumulation following IκBα turnover and shuttling. Nuclear import assays, NLS mutagenesis, subcellular fractionation, nuclear export assay (CRM1 dependence), co-immunoprecipitation in B-cell lines Molecular and Cellular Biology Medium 11416157
2025 N4BP3 interacts with IκBα and promotes K48-linked ubiquitination of IκBα, leading to NF-κB pathway activation; N4BP3 overexpression elevates K48-linked ubiquitination of IκBα and increases pro-inflammatory cytokine expression in THP-1 cells, whereas N4BP3 knockdown reduces IκBα ubiquitination and colitis severity in vivo. Co-immunoprecipitation, K48-linked ubiquitination assay, N4BP3 overexpression/knockdown, DSS-induced colitis mouse model, AAV-mediated knockdown Journal of Inflammation Research Medium 40487287
2022 TRIM67 competes with IκBα for binding to β-TrCP, thereby inhibiting β-TrCP-mediated ubiquitination and degradation of IκBα and suppressing TNFα-triggered NF-κB activation; Trim67 deletion in MEFs promotes inflammatory gene expression after TNFα. Co-immunoprecipitation (TRIM67–β-TrCP–IκBα competition), Trim67 knockdown/knockout, TNFα stimulation assays, NF-κB reporter Frontiers in Immunology Medium 35273593
2017 FBXO32 F-box protein stabilizes and polyubiquitinates IκBα under genotoxic stress and inflammatory conditions, promoting proteasomal degradation of IκBα and NF-κB activation; FBXO32 also regulates basal IκBα levels in unstressed cells. Co-immunoprecipitation, ubiquitination assay, FBXO32 overexpression/knockdown, genotoxic stress (doxorubicin) and LPS treatment The International Journal of Biochemistry & Cell Biology Low 28970077
1998 IκBα contains distinct functional domains for cytoplasmic versus nuclear regulation of c-Rel: the N-terminal and central ankyrin regions mediate cytoplasmic retention and NLS masking, while the central ankyrin domain and negatively charged residues in the C-terminal PEST domain are required for nuclear regulation of c-Rel. Domain-deletion mutagenesis of IκBα, subcellular fractionation, transcriptional reporter assays Molecular and Cellular Biology Medium 9488436
2003 IκBα cytoplasmic sequestration of p65 is sufficient to translocate nuclear corepressors N-CoR/SMRT to the cytoplasm and upregulate Notch-dependent transcription; p65 and IκBα can directly bind SMRT, and this interaction is inhibited by CBP/p300 coactivator in a dose-dependent manner and by TNFα treatment, suggesting p65 acetylation modulates this cross-talk. Co-immunoprecipitation (p65–IκBα–SMRT), subcellular fractionation, reporter assays, TNFα stimulation Molecular Biology of the Cell Medium 12589049
1999 Purified protein kinase CKII directly phosphorylates IκBα at both S32 and S36 in vitro, and CKII immunoprecipitated from cells specifically associates with IκBα; this CKII kinase activity is biochemically distinct from the IKKα/β-containing signalsome complex. In vitro phosphorylation assay with purified CKII, immunoprecipitation of endogenous CKII-IκBα complex, phospho-site mapping Journal of Molecular Biology Medium 10398585
2014 COMMD1/Murr1 stabilizes IκBα protein by increasing its interaction with IκBα and inhibiting proteasomal degradation in latently HIV-1-infected myeloid cells; COMMD1 induction by the PI3K-JAK pathway attenuates NF-κB signaling and enhances HIV-1 latency. Co-immunoprecipitation (COMMD1–IκBα), proteasome inhibitor assays, PI3K-JAK pathway inhibitors, Western blot in matched parental/latently infected cell lines Journal of Virology Medium 25520503
2011 Dimethylfumarate (DMF) reduces intracellular glutathione and induces glutathionylation of IκBα (IκBα-SSG), which inhibits IκBα degradation, NF-κB p65 nuclear entry, and NF-κB/DNA binding in airway smooth muscle cells; these effects are reversed by addition of GSH-OEt, confirming glutathionylation as the inhibitory modification. Co-immunoprecipitation of glutathionylated IκBα, EMSA (NF-κB/DNA binding), immunofluorescence, Western blot, GSH-OEt rescue The European Respiratory Journal Medium 21719482
2002 PPARα activation potentiates p65-stimulated IκBα transcription in a ligand-dependent manner requiring the NF-κB and Sp1 sites in the IκBα promoter; this mechanism requires the coactivator DRIP205 but not CBP/p300; ChIP assays show PPARα activation enhances occupancy of the NF-κB response element in the IκBα promoter in vivo. Transient transfection luciferase assays, site-directed mutagenesis of NF-κB/Sp1 promoter sites, chromatin immunoprecipitation, dominant-negative DRIP205 overexpression Molecular Endocrinology Medium 11981037
2009 Nur77 (orphan nuclear receptor) directly binds to a Nur77 response element in the IκBα promoter and transcriptionally upregulates IκBα expression; Nur77 overexpression increases IκBα protein ~4-fold, whereas dominant-negative Nur77 (lacking transactivation domain) has no effect; the resulting IκBα upregulation suppresses TNFα- and IL-1β-induced NF-κB activation and endothelial cell adhesion molecule expression. Adenoviral overexpression, dominant-negative Nur77, IκBα promoter-reporter assay, ChIP (Nur77 binding to IκBα promoter), Western blot, NF-κB activation assays Circulation Research Medium 19213954
2008 Tumor suppressor SMAR1 binds directly to the matrix attachment region (MAR) site in the IκBα promoter, recruits a corepressor complex, and represses IκBα transcription; this generates NF-κB complexes (p65-p50) that are DNA-binding competent but phosphorylation- and transactivation-deficient, suppressing a subset of NF-κB target genes involved in tumorigenesis. ChIP (SMAR1 binding to IκBα promoter MAR site), promoter-reporter assay, SMAR1 overexpression/siRNA, NF-κB target gene array The Journal of Biological Chemistry Medium 18981184

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Structure of an IkappaBalpha/NF-kappaB complex. Cell 713 9865693
1998 Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature 567 9859996
2022 Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα. Cell metabolism 350 36007522
2011 Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clinical microbiology reviews 294 21734245
1999 Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha. Oncogene 264 10340377
1996 Role of IkappaBalpha ubiquitination in signal-induced activation of NFkappaB in vivo. The Journal of biological chemistry 210 8631829
2010 NFKBIA deletion in glioblastomas. The New England journal of medicine 204 21175304
2004 Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. The Journal of biological chemistry 177 15322087
2008 NF-kappaB dictates the degradation pathway of IkappaBalpha. The EMBO journal 174 18401342
2007 NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases. Histology and histopathology 162 17701919
2003 IkappaB kinase-independent IkappaBalpha degradation pathway: functional NF-kappaB activity and implications for cancer therapy. Molecular and cellular biology 135 14585967
2020 TRIM22 activates NF-κB signaling in glioblastoma by accelerating the degradation of IκBα. Cell death and differentiation 129 32814880
2019 Curcumin attenuates MSU crystal-induced inflammation by inhibiting the degradation of IκBα and blocking mitochondrial damage. Arthritis research & therapy 124 31455356
2010 Molecular mechanisms of system control of NF-kappaB signaling by IkappaBalpha. Biochemistry 119 20055496
2009 The orphan nuclear receptor Nur77 suppresses endothelial cell activation through induction of IkappaBalpha expression. Circulation research 112 19213954
2004 The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. The Journal of experimental medicine 102 15337789
2000 IkappaBalpha and IkappaBalpha /NF-kappa B complexes are retained in the cytoplasm through interaction with a novel partner, RasGAP SH3-binding protein 2. The Journal of biological chemistry 99 10969074
1999 Characterization of IkappaBalpha nuclear import pathway. The Journal of biological chemistry 99 10037782
2002 DNA binding-independent induction of IkappaBalpha gene transcription by PPARalpha. Molecular endocrinology (Baltimore, Md.) 98 11981037
2001 Phosphorylation by the protein kinase CK2 promotes calpain-mediated degradation of IkappaBalpha. Journal of immunology (Baltimore, Md. : 1950) 93 11673497
2003 IkappaBalpha and p65 regulate the cytoplasmic shuttling of nuclear corepressors: cross-talk between Notch and NFkappaB pathways. Molecular biology of the cell 83 12589049
2010 Regulation of IkappaBalpha function and NF-kappaB signaling: AEBP1 is a novel proinflammatory mediator in macrophages. Mediators of inflammation 80 20396415
2007 Tyrosine nitration of IkappaBalpha: a novel mechanism for NF-kappaB activation. Biochemistry 80 17910475
2021 Exosome-based delivery of super-repressor IκBα ameliorates kidney ischemia-reperfusion injury. Kidney international 79 34051264
2001 Control of IkappaBalpha proteolysis by the ubiquitin-proteasome pathway. Biochimie 79 11295496
2015 β₁-adrenoceptor stimulation promotes LPS-induced cardiomyocyte apoptosis through activating PKA and enhancing CaMKII and IκBα phosphorylation. Critical care (London, England) 74 25887954
2008 A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Human mutation 67 18412279
2013 Functional genetic variation in NFKBIA and susceptibility to childhood asthma, bronchiolitis, and bronchopulmonary dysplasia. Journal of immunology (Baltimore, Md. : 1950) 64 23487427
2002 Polymorphic variants of NFKB1 and its inhibitory protein NFKBIA, and their involvement in sporadic breast cancer. Cancer letters 64 12406554
2021 Transcriptional repression of NFKBIA triggers constitutive IKK- and proteasome-independent p65/RelA activation in senescence. The EMBO journal 63 33459422
2019 miR-196a-5p promotes metastasis of colorectal cancer via targeting IκBα. BMC cancer 59 30621631
2020 Post-translational Modifications of IκBα: The State of the Art. Frontiers in cell and developmental biology 58 33224945
2006 Efficient nuclear export of p65-IkappaBalpha complexes requires 14-3-3 proteins. Journal of cell science 57 16931600
2018 MicroRNA-216a induces endothelial senescence and inflammation via Smad3/IκBα pathway. Journal of cellular and molecular medicine 55 29512862
2012 Effects of NFKB1 and NFKBIA gene polymorphisms on susceptibility to environmental factors and the clinicopathologic development of oral cancer. PloS one 54 22509384
2012 Heterologous SUMO-2/3-ubiquitin chains optimize IκBα degradation and NF-κB activity. PloS one 54 23284737
2022 Elevated expression of the rhythm gene NFIL3 promotes the progression of TNBC by activating NF-κB signaling through suppression of NFKBIA transcription. Journal of experimental & clinical cancer research : CR 51 35180863
2017 Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency. Journal of clinical immunology 49 28597146
2008 Pre-folding IkappaBalpha alters control of NF-kappaB signaling. Journal of molecular biology 49 18511071
2013 A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy. Journal of clinical immunology 47 23708964
2025 N4BP3 Activates TLR4-NF-κB Pathway in Inflammatory Bowel Disease by Promoting K48-Linked IκBα Ubiquitination. Journal of inflammation research 44 40487287
1992 Chromosomal localization of the genes encoding the p50/p105 subunits of NF-kappa B (NFKB2) and the I kappa B/MAD-3 (NFKBI) inhibitor of NF-kappa B to 4q24 and 14q13, respectively. Genomics 44 1427874
2022 TRIM67 Suppresses TNFalpha-Triggered NF-kB Activation by Competitively Binding Beta-TrCP to IkBa. Frontiers in immunology 39 35273593
2018 USP14-mediated IκBα degradation exacerbates NF-κB activation and IL-1β-stimulated chondrocyte dedifferentiation. Life sciences 39 30550885
2013 The p97-UFD1L-NPL4 protein complex mediates cytokine-induced IκBα proteolysis. Molecular and cellular biology 39 24248593
2023 Histone demethylase KDM5B licenses macrophage-mediated inflammatory responses by repressing Nfkbia transcription. Cell death and differentiation 38 36914768
2022 Baicalin regulates TLR4/IκBα/NFκB signaling pathway to alleviate inflammation in Doxorubicin related cardiotoxicity. Biochemical and biophysical research communications 38 36375245
2021 ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling. Journal of experimental & clinical cancer research : CR 38 33962660
2013 Effects of NFKB1 and NFKBIA gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathological features. PloS one 38 23457512
1995 Structure and evolution of the human IKBA gene. Genomics 38 8666399
2011 IκBα glutathionylation and reduced histone H3 phosphorylation inhibit eotaxin and RANTES. The European respiratory journal 36 21719482
2001 Cell-specific association and shuttling of IkappaBalpha provides a mechanism for nuclear NF-kappaB in B lymphocytes. Molecular and cellular biology 36 11416157
2020 circ-CEP85L suppresses the proliferation and invasion of gastric cancer by regulating NFKBIA expression via miR-942-5p. Journal of cellular physiology 34 32026471
2019 Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and risk for early-onset coronary artery disease. Immunology letters 32 30902734
2009 The IkappaBalpha gene is a peroxisome proliferator-activated receptor cardiac target gene. The FEBS journal 32 19438714
2023 Fructose-1,6-bisphosphatase 1 dephosphorylates IκBα and suppresses colorectal tumorigenesis. Cell research 31 36646759
1999 Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro. Journal of molecular biology 31 10398585
2015 Anatomy of a negative feedback loop: the case of IκBα. Journal of the Royal Society, Interface 30 26311312
2020 Histone deacetylase 4 inhibits NF-κB activation by facilitating IκBα sumoylation. Journal of molecular cell biology 29 32770227
2010 Fibromodulin suppresses nuclear factor-kappaB activity by inducing the delayed degradation of IKBA via a JNK-dependent pathway coupled to fibroblast apoptosis. The Journal of biological chemistry 29 21156791
1995 The relocalization of v-Rel from the nucleus to the cytoplasm coincides with induction of expression of Ikba and nfkb1 and stabilization of I kappa B-alpha. Journal of virology 28 7983736
2017 DNA and IκBα Both Induce Long-Range Conformational Changes in NFκB. Journal of molecular biology 27 28249778
2023 USP39 Regulates NF-κB-Mediated Inflammatory Responses through Deubiquitinating K48-Linked IκBα. Journal of immunology (Baltimore, Md. : 1950) 26 36651806
2014 Genetic polymorphism of NFKB1 and NFKBIA genes and liver cancer risk: a nested case-control study in Shanghai, China. BMJ open 26 24578542
2009 Suppression of IkappaBalpha increases the expression of matrix metalloproteinase-2 in human ciliary muscle cells. Molecular vision 26 19816602
2015 Genetic Variation in NFKB1 and NFKBIA and Susceptibility to Coronary Artery Disease in a Chinese Uygur Population. PloS one 25 26075620
2010 Mutations of NFKBIA in biopsy specimens from Hodgkin lymphoma. Cancer genetics and cytogenetics 25 20193848
2017 Association of NFKB1 and NFKBIA gene polymorphisms with susceptibility of gastric cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 24 28670959
2010 Association of the NFKBIA gene polymorphisms with susceptibility to autoimmune and inflammatory diseases: a meta-analysis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 24 20495844
2019 Genetic Association between NFKBIA and NFKB1 Gene Polymorphisms and the Susceptibility to Head and Neck Cancer: A Meta-Analysis. Disease markers 23 31612070
2007 Deguelin inhibits expression of IkappaBalpha protein and induces apoptosis of B-CLL cells in vitro. Leukemia 23 17568818
2005 Regulation of IkappaBalpha expression involves both NF-kappaB and the MAP kinase signaling pathways. Journal of inflammation (London, England) 23 16207380
2014 Ribosomal protein S3 interacts with the NF-κB inhibitor IκBα. FEBS letters 22 24457201
2007 A cell-based assay for IkappaBalpha stabilization using a two-color dual luciferase-based sensor. Assay and drug development technologies 22 17355202
1998 Distinct domains of IkappaBalpha regulate c-Rel in the cytoplasm and in the nucleus. Molecular and cellular biology 22 9488436
1998 Relationship between IkappaBalpha constitutive expression, TNFalpha synthesis, and apoptosis in EBV-infected lymphoblastoid cells. Oncogene 22 9794238
2021 SPOCK1 promotes metastasis in pancreatic cancer via NF-κB-dependent epithelial-mesenchymal transition by interacting with IκB-α. Cellular oncology (Dordrecht, Netherlands) 21 34855159
2020 Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency. The Journal of clinical investigation 21 32750042
2019 Constant hypoxia inhibits osteoclast differentiation and bone resorption by regulating phosphorylation of JNK and IκBα. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 21 30604211
2008 Tumor suppressor SMAR1 represses IkappaBalpha expression and inhibits p65 transactivation through matrix attachment regions. The Journal of biological chemistry 21 18981184
2018 Bmi1 Regulates IκBα Degradation via Association with the SCF Complex. Journal of immunology (Baltimore, Md. : 1950) 20 30209188
2018 β-TrCP Restricts Lipopolysaccharide (LPS)-Induced Activation of TRAF6-IKK Pathway Upstream of IκBα Signaling. Frontiers in immunology 20 30619291
2015 GRK6 phosphorylates IκBα at Ser(32)/Ser(36) and enhances TNF-α-induced inflammation. Biochemical and biophysical research communications 20 25881508
2015 p97/VCP promotes Cullin-RING-ubiquitin-ligase/proteasome-dependent degradation of IκBα and the preceding liberation of RelA from ubiquitinated IκBα. Journal of cellular and molecular medicine 20 26463447
2015 Common Polymorphisms in the NFKBIA Gene and Cancer Susceptibility: A Meta-Analysis. Medical science monitor : international medical journal of experimental and clinical research 20 26488500
2023 Exosomal miR-196a-5p enhances radioresistance in lung cancer cells by downregulating NFKBIA. The Kaohsiung journal of medical sciences 19 36912495
2019 Hypoxia induces rapid, STAT3 and ROS dependent, mitochondrial translocation of RelA(p65) and IκBα. Bioscience reports 19 31484794
2023 The Circadian Nobiletin-ROR Axis Suppresses Adipogenic Differentiation and IκBα/NF-κB Signaling in Adipocytes. Nutrients 18 37764703
2022 Genetic variants in the NF-κB signaling pathway (NFKB1, NFKBIA, NFKBIZ) and risk of critical outcome among COVID-19 patients. Human immunology 18 35777990
1999 Structural analysis, expression, and chromosomal localization of the mouse ikba gene. Immunogenetics 18 10199915
2024 USP9X-enriched MSC-sEV inhibits LSEC angiogenesis in MASH mice by downregulating the IκBα/NF-κB/Ang-2 pathway. Pharmacological research 17 39427871
2021 Dynamic chromatin association of IκBα is regulated by acetylation and cleavage of histone H4. EMBO reports 17 34224210
2017 FBXO32 activates NF-κB through IκBα degradation in inflammatory and genotoxic stress. The international journal of biochemistry & cell biology 17 28970077
2014 COMMD1/Murr1 reinforces HIV-1 latent infection through IκB-α stabilization. Journal of virology 17 25520503
2010 Interplay between BCL10, MALT1 and IkappaBalpha during T-cell-receptor-mediated NFkappaB activation. Journal of cell science 17 20551178
2005 Germline mutations and polymorphisms in the NFKBIA gene in Hodgkin lymphoma. International journal of cancer 17 15858823
2024 Cadmium promoted LPS-induced inflammation through TLR4/IκBα/NFκ-B signaling by increasing ROS-mediated incomplete autophagy. Ecotoxicology and environmental safety 16 38696874
2007 HLA, NFKB1 and NFKBIA gene polymorphism profile in autoimmune diabetes mellitus patients. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 16 17318773
2006 Deguelin inhibits expression of IkappaBalpha protein in Raji and U937 cells. Acta pharmacologica Sinica 16 16539850
2012 Regulation and function of nuclear IκBα in inflammation and cancer. American journal of clinical and experimental immunology 15 23885315

Missed literature

Know a paper Affinage missed for NFKBIA? Flag it for the maintainers and the community.

No submissions yet.