Affinage

NFKBIA

NF-kappa-B inhibitor alpha · UniProt P25963

Length
317 aa
Mass
35.6 kDa
Annotated
2026-04-29
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IκBα (NFKBIA) is the principal cytoplasmic inhibitor of NF-κB, functioning as a multi-layered negative regulator whose degradation, re-synthesis, and nuclear shuttling collectively set the amplitude and duration of NF-κB-dependent transcription. Its six-ankyrin-repeat domain binds the p50/p65 heterodimer, masking the p65 nuclear localization signal and occluding the DNA-binding cleft; signal-induced phosphorylation at S32/S36 by IKK (and additionally by GRK6 or metabolic kinases such as HK2 at T291) triggers recognition by the SCFβ-TrCP ubiquitin ligase, K48-linked polyubiquitination (augmented by hybrid SUMO-2/3–ubiquitin chains and facilitated by the p97–UFD1L–NPL4 ATPase), and 26S proteasomal degradation, while free IκBα undergoes constitutive, ubiquitin-independent proteasomal turnover governed by CK2-mediated PEST-domain phosphorylation and μ-calpain cleavage (PMID:9865693, PMID:8631829, PMID:9859996, PMID:18401342, PMID:23284737, PMID:24248593, PMID:36007522). Newly synthesized IκBα enters the nucleus via an importin α/β-dependent piggyback mechanism to strip NF-κB from DNA, and 14-3-3 proteins then facilitate nuclear export of the IκBα–NF-κB complex, completing a transcription-driven negative-feedback loop whose dynamics are shaped by IκBα nuclear trafficking rates as much as by its re-expression (PMID:10037782, PMID:16931600, PMID:26311312). Intestinal epithelial-specific loss of Nfkbia causes constitutive NF-κB activation, mucosal inflammation, crypt hyperplasia, and Paneth-cell depletion, phenocopying hallmarks of inflammatory bowel disease (PMID:32222043).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 High

    Establishing that the ankyrin repeat domain is the modular unit required for Rel-protein binding and DNA-binding inhibition resolved the question of which IκBα regions mediate NF-κB sequestration.

    Evidence Domain deletion, native gel, cross-linking, and DNA-binding inhibition assays

    PMID:8334994

    Open questions at the time
    • Atomic-resolution contacts between ankyrin repeats and NF-κB dimers unknown
    • Specificity determinants for p65 vs. other Rel subunits unresolved
  2. 1996 High

    Demonstration that TNFα-induced IκBα phosphorylation at S32/S36 is a prerequisite for polyubiquitination and proteasomal degradation established the ordered signal-dependent destruction mechanism, while concurrent identification of CK2-mediated PEST-domain phosphorylation controlling basal turnover revealed a parallel, stimulus-independent degradation pathway.

    Evidence S32A/S36A mutagenesis, anti-ubiquitin immunoblotting, proteasome inhibition (signal pathway); affinity-purified kinase identification, in-gel kinase assay, PEST-site mutagenesis, stable cell lines (basal pathway)

    PMID:8631829 PMID:8657113

    Open questions at the time
    • Identity of the E3 ligase unknown
    • Whether CK2-phosphorylated IκBα is degraded by proteasome or another protease unresolved
  3. 1998 High

    The crystal structure of IκBα bound to p50/p65 at 2.7 Å and the biochemical identification of β-TrCP as the SCF receptor subunit for phospho-IκBα together provided the first complete structural and enzymatic framework for signal-dependent IκBα destruction.

    Evidence X-ray crystallography (structure); immunoaffinity purification, nanoelectrospray MS, in vitro ubiquitination, dominant-negative overexpression (β-TrCP identification)

    PMID:9859996 PMID:9865693

    Open questions at the time
    • Ubiquitin chain linkage type on IκBα not yet characterized
    • Post-ubiquitination extraction mechanism unknown
  4. 1999 High

    Discovery that IκBα is actively imported into the nucleus via importin α/β and Ran, and that the SCFβ-TrCP complex requires an intact DSGXXS phosphodegron including D31, defined IκBα as a nuclear shuttling protein and refined the molecular requirements for ligase recognition.

    Evidence Nuclear import assays with energy/importin depletion (import); DSGXXS mutagenesis and in vitro ubiquitination (degron)

    PMID:10037782 PMID:10514433

    Open questions at the time
    • Piggyback import partner identity unknown
    • CRM1 vs. other exportin dependence of nuclear export unresolved
  5. 2001 High

    Identification of μ-calpain as the protease executing CK2-dependent basal IκBα degradation, and the finding that NEDD8-modified Cullin-1 enhances SCF ligase activity toward IκBα, added protease and post-translational regulatory layers to both degradation arms.

    Evidence In vitro CK2-phosphorylation/calpain assay with triple PEST mutant (calpain); NEDD8 modification assays on SCF complex (NEDD8)

    PMID:11295496 PMID:11673497

    Open questions at the time
    • Relative contribution of calpain vs. proteasome to basal turnover in different cell types unclear
    • NEDD8 cycling dynamics on SCFβ-TrCP during IκBα degradation not kinetically resolved
  6. 2006 High

    The finding that 14-3-3 proteins bind both p65 and IκBα and facilitate nuclear export of the p65–IκBα complex solved the question of how negative-feedback IκBα removes NF-κB from the nucleus.

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

    PMID:16931600

    Open questions at the time
    • Structural basis of 14-3-3 engagement with the IκBα–p65 complex unknown
    • Whether phosphorylation of 14-3-3 binding sites on p65 or IκBα is dynamically regulated unresolved
  7. 2008 High

    Biochemical reconstitution showing that NF-κB binding masks the PEST domain and switches IκBα from rapid ubiquitin-independent to slow ubiquitin-dependent degradation, together with biophysical evidence that coupled folding–binding of ankyrin repeats 5–6 is essential for both NF-κB affinity and proteasomal sensitivity, unified the two degradation pathways into a single structural framework.

    Evidence Reconstituted free vs. bound IκBα degradation assays, SPR/ITC of stabilizing AR5-6 mutants, cell-based NF-κB activity

    PMID:18401342 PMID:18511071

    Open questions at the time
    • Proteasomal recognition elements on free IκBα (intrinsically disordered regions vs. PEST) not structurally mapped
    • Whether other I-κB family members share coupled-folding degradation logic untested
  8. 2012 High

    Discovery that hybrid SUMO-2/3–ubiquitin chains form on IκBα and enhance proteasomal degradation beyond ubiquitin-only chains established a novel mixed-chain signal amplifying the canonical destruction pathway.

    Evidence In vitro ubiquitination, TUBE pulldown, Ubc9 siRNA, NF-κB reporter

    PMID:23284737

    Open questions at the time
    • Specific SUMO acceptor lysines on IκBα not mapped
    • SUMO-targeted ubiquitin ligase identity not identified
  9. 2013 High

    The p97/VCP–UFD1L–NPL4 ATPase complex was shown to extract polyubiquitinated IκBα for proteasomal delivery, filling the mechanistic gap between ubiquitination and actual proteolysis.

    Evidence Co-IP of p97 with ubiquitinated IκBα and SCFβ-TrCP, siRNA knockdown, ATPase-dead p97 mutant

    PMID:24248593

    Open questions at the time
    • Whether p97 acts before or after IκBα dissociates from NF-κB not resolved
    • Kinetic contribution of p97 relative to direct proteasomal capture unknown
  10. 2015 Medium

    Computational modeling validated by live imaging showed that nuclear import/export rates of free IκBα, not just NF-κB-driven re-expression, are rate-limiting for negative feedback, while GRK6 was identified as an additional S32/S36 kinase in macrophages, broadening the kinase repertoire beyond IKK.

    Evidence Computational simulations with single-cell live imaging (feedback dynamics); in vitro kinase assay, GRK6 KO macrophages (kinase)

    PMID:25881508 PMID:26311312

    Open questions at the time
    • GRK6 contribution relative to IKK not quantified in vivo
    • Whether GRK6-mediated phosphorylation is stimulus-specific or tissue-specific unresolved
    • Model predictions for multi-stimulus NF-κB dynamics not experimentally tested
  11. 2020 High

    Multiple regulators were identified that modulate IκBα ubiquitination at the ligase or competing-modification level: TRIM22 promotes K48-linked ubiquitination and also activates IKK via K63-ubiquitination of NEMO; HDAC4 acts as a SUMO E3 ligase sumoylating IκBα at K21 to block ubiquitination at the same residue; and intestinal-specific Nfkbia knockout demonstrated that sustained loss of IκBα causes IBD-like pathology.

    Evidence RING-domain mutants, K48/K63-specific ubiquitin assays (TRIM22); SUMO E3 assay, K21 mutagenesis, HDAC4 localization mutants (HDAC4); tissue-specific Nfkbia KO mice and organoids (IBD model)

    PMID:32222043 PMID:32770227 PMID:32814880

    Open questions at the time
    • Whether HDAC4 sumoylation of IκBα occurs at baseline or is signal-regulated unclear
    • TRIM22 vs. β-TrCP substrate channeling not determined
    • Mechanism connecting constitutive NF-κB to Paneth-cell depletion not molecularly resolved
  12. 2022 High

    Identification of hexokinase 2 (HK2) as a direct IκBα T291 kinase linking metabolic state (high glucose) to μ-calpain-mediated IκBα degradation and PD-L1 upregulation in glioblastoma revealed a metabolic–immune evasion axis operating through basal IκBα turnover.

    Evidence In vitro kinase assay, T291A mutant, HK inhibitor, Co-IP, in vivo tumor model

    PMID:36007522

    Open questions at the time
    • Whether HK2-mediated IκBα phosphorylation occurs in non-tumor cells unknown
    • Structural basis for HK2 kinase activity toward IκBα not determined
  13. 2023 High

    Discovery of FBP1 as a direct phosphatase dephosphorylating IκBα at S32/S36, USP39 as a K48-specific deubiquitinase stabilizing basal IκBα, and KDM5B as a histone demethylase that suppresses NFKBIA transcription added three new regulatory nodes—dephosphorylation, deubiquitination, and epigenetic silencing—to the IκBα circuit.

    Evidence In vitro dephosphorylation assay, phosphoproteomics, MD simulations (FBP1); K48-specific DUB assay, USP39 KO macrophages and sepsis model (USP39); KDM5B ChIP-seq, ATAC-seq, KO mouse arthritis/endotoxin model (KDM5B)

    PMID:36646759 PMID:36651806 PMID:36914768

    Open questions at the time
    • FBP1 substrate selectivity among IKK targets unknown
    • Whether USP39 DUB activity is stimulus-regulated not tested
    • KDM5B recruitment mechanism to the NFKBIA locus unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple kinase inputs (IKK, GRK6, HK2, CK2), competing ubiquitin/SUMO modifications, opposing enzymes (FBP1, USP39, HDAC4), and epigenetic regulators (KDM5B) are integrated in space and time to shape IκBα dynamics in specific cell types and disease contexts remains unresolved.
  • No integrated quantitative model incorporating all identified kinase and E3/DUB inputs
  • Tissue-specific relative contributions of alternative degradation pathways not mapped
  • Structural basis of ubiquitin-independent proteasomal recognition of free IκBα not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 3
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-168256 Immune System 4
Partners
BTRCFBP1HDAC4NFKB1RELAUSP39VCPYWHAZ
Complex memberships
NF-κB–IκBα cytoplasmic inhibitory complexSCFβ-TrCP E3 ubiquitin ligase (substrate)

Evidence

Reading pass · 35 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 the NF-κB p50/p65 heterodimer at 2.7 Å resolution revealed that six ankyrin repeats contact discontinuous patches on the C-terminal Rel homology domains of NF-κB, the first two repeats cover the p65 nuclear localization signal, and the sixth repeat position indicates full-length IκBα would occlude the NF-κB DNA-binding cleft. X-ray crystallography Cell High 9865693
1998 The F-box/WD-domain protein β-TrCP (E3RSIκBα) was identified as the receptor subunit of the phospho-IκBα ubiquitin ligase; it binds specifically to phosphorylated IκBα and promotes its in vitro ubiquitination together with E1 and UBC5C (E2); an F-box-deletion dominant-negative mutant blocked IκBα degradation and NF-κB activation in vivo. Immunoaffinity purification, nanoelectrospray mass spectrometry, in vitro ubiquitination assay, dominant-negative overexpression Nature High 9859996
1996 Signal-induced NF-κB activation requires phosphorylation-dependent ubiquitination of IκBα: TNFα stimulation causes rapid accumulation of polyubiquitinated IκBα forms that dissociate from NF-κB when proteasomal degradation is inhibited; an S32A/S36A mutant IκBα is neither phosphorylated nor ubiquitinated in response to TNFα, demonstrating that N-terminal phosphorylation is prerequisite for ubiquitination and proteasomal degradation. Proteasome inhibition, ubiquitin carboxyl-terminal hydrolase treatment, anti-ubiquitin immunoblotting, epitope-tagged ubiquitin co-expression The Journal of Biological Chemistry High 8631829
1996 Casein kinase II (CKIIα) phosphorylates IκBα in the C-terminal PEST domain at residues T291, S283, and T299; mutation of these sites increases intrinsic protein stability without affecting TNFα-inducible degradation, indicating that CKII-mediated constitutive phosphorylation controls basal IκBα turnover independently of the signal-induced N-terminal phosphorylation pathway. Affinity chromatography kinase isolation, in-gel kinase assay, deletion and point mutagenesis, stable cell line expression under tetracycline-responsive promoter Molecular and Cellular Biology High 8657113
1999 IκBα is actively and constitutively imported into the nucleus via an energy-dependent, importin α/β- and Ran-dependent mechanism that requires the ankyrin repeat domain of IκBα and additional piggy-back factor(s) containing a basic NLS; binding of IκBα to NF-κB retains IκBα in the cytoplasm. Nuclear import assays, selective depletion from cell extracts with ankyrin repeat domain, inhibition of energy and importin function The Journal of Biological Chemistry High 10037782
2008 Two distinct degradation pathways control IκBα levels: free IκBα is rapidly degraded by a ubiquitin-independent, proteasomal mechanism mediated by the C-terminal PEST domain; NF-κB binding to IκBα masks the PEST domain and switches degradation to a slow, IKK phosphorylation- and ubiquitination-dependent pathway. Both free and NF-κB-bound IκBα are equally good IKK substrates, but NF-κB binding stabilizes IκBα, making the bound form the preferred substrate for signal-dependent degradation. Biochemical reconstitution, mutant analysis, in vivo degradation assays The EMBO Journal High 18401342
1999 The SCF complex containing F-box protein FWD1 (mouse β-TrCP) recognizes the DSGXXS motif of IκBα; beyond phosphorylation at S32/S36, an acidic residue at position D31 is required for FWD1 binding and subsequent ubiquitination of IκBα; Skp1 residues 61–143 mediate binding to FWD1. Mutagenesis of IκBα DSGXXS motif, in vitro binding and ubiquitination assays, deletion analysis of Skp1 The Journal of Biological Chemistry High 10514433
2001 CK2 phosphorylation of IκBα PEST domain residues S283, T291, and T299 promotes μ-calpain-mediated degradation of IκBα in IgM+ B cells; CK2 inhibition decreases IκBα turnover and reduces basal NF-κB levels; a triple PEST-mutant IκBα (S283A/T291A/T299A) resists calpain-mediated degradation even after CK2 treatment. In vitro CK2 phosphorylation/calpain degradation assay, CK2 inhibitor apigenin, point mutagenesis Journal of Immunology High 11673497
2000 IKK phosphorylation sites (S32/S36) on IκBα control only signal-dependent but not signal-independent turnover; C-terminal CK2 phosphorylation sites are required for both signal-dependent and signal-independent turnover of IκBα; a full-length IκBα mutant unable to associate with RelA/p65 demonstrates these degradation mechanisms operate on free IκBα. IκBα mutants unable to bind NF-κB combined with IKK inhibition and CKII site mutagenesis, pulse-chase degradation assays The Journal of Biological Chemistry Medium 10801847
2001 The NEDD8 modification of Cullin-1 (Cul-1) within the SCFβ-TrCP complex enhances IκBα ubiquitin ligase activity, thereby promoting IκBα proteolysis; NEDD8 functions as a covalent modifier of the SCF complex that potentiates IκBα degradation. Biochemical analysis of SCF complex activity, NEDD8 modification assays Biochimie Medium 11295496
2006 14-3-3 proteins physically interact with p65 (at residues 38–44 and 278–283) and IκBα (at residues 60–65), facilitate nuclear export of p65–IκBα complexes, and are required for proper termination of NF-κB signaling; dominant-negative 14-3-3 causes nuclear accumulation of p65–IκBα complexes and renders NF-κB-dependent genes unresponsive to TNFα. Co-immunoprecipitation, mapping of interaction domains by mutagenesis, dominant-negative 14-3-3 overexpression, chromatin immunoprecipitation Journal of Cell Science High 16931600
2013 The p97/VCP ATPase, together with its cofactors UFD1L and NPL4, mediates post-ubiquitinational regulation of IκBα proteolysis after TNFα or IL-1β treatment; the p97 complex associates with ubiquitinated IκBα via interactions between p97 and SCFβ-TrCP and between the polyubiquitin-binding domain of UFD1L and polyubiquitinated IκBα; ATPase activity of p97 is essential for this function. Co-immunoprecipitation, siRNA knockdown, ATPase-dead mutant of p97, NF-κB reporter assays Molecular and Cellular Biology High 24248593
2012 Hybrid SUMO-2/3–ubiquitin chains form on IκBα after TNFα stimulation; SUMO-2/3 modification promotes ubiquitin chain formation on IκBα; heterologous SUMO-2/3–ubiquitin chains support more efficient 26S proteasome-mediated degradation of IκBα than chains of either modification alone; depletion of Ubc9 (SUMO E2) delays TNFα-induced IκBα proteolysis and NF-κB-dependent transcription. In vitro ubiquitination assay, ubiquitin-trap (TUBE) pulldown, Ubc9 siRNA, NF-κB reporter assays PLoS One High 23284737
2008 Pre-folding the IκBα ankyrin repeats 5–6 by stabilizing mutations slows ubiquitin-independent free IκBα degradation both in vitro and in cells, reduces NF-κB binding affinity (measured by SPR and ITC), and results in incomplete inhibition of basal NF-κB, demonstrating that coupled folding–binding of the ankyrin repeat domain is critical for IκBα's precise control of NF-κB. Stabilizing mutations in AR6, surface plasmon resonance, isothermal titration calorimetry, in vitro degradation assay, cell-based NF-κB activity measurements Journal of Molecular Biology High 18511071
2007 Ionizing radiation activates NF-κB by causing nitration of IκBα tyrosine 181 (via constitutive NO synthase activation), which dissociates intact IκBα from NF-κB without requiring IKK-dependent phosphorylation or proteolytic degradation of IκBα; Y181 participates in noncovalent interactions with p50 that stabilize the IκBα–NF-κB complex. Ionizing radiation of cells, NOS inhibition, mass spectrometry-based detection of nitrated Y181, NF-κB reporter assay, structural analysis of crystal structure contacts Biochemistry Medium 17910475
2003 IκBα binds to and inhibits cyclin-dependent kinase 4 (CDK4) through its N-terminal four ankyrin repeats; IκBα and INK4 proteins compete for CDK4 binding; binding/inhibition potencies are comparable to INK4 proteins, suggesting cross-talk between the NF-κB/IκBα and p16/CDK4/Rb pathways. Yeast two-hybrid assay, in vitro kinase inhibition assay, in vitro binding assay, competition assay with INK4 proteins, CDK4 mutant analysis Biochemistry Medium 14621993
2001 IκBα-p65 complexes in the cytoplasm can translocate nuclear co-repressors SMRT/N-CoR to the cytoplasm; p65 and IκBα directly bind SMRT; CBP coactivator and TNFα treatment (leading to p65 acetylation) inhibit this interaction, providing a mechanism by which IκBα cytoplasmic sequestration of p65 upregulates Notch-dependent gene transcription. Co-immunoprecipitation, cytoplasmic localization assays, TNFα stimulation, CBP overexpression Molecular Biology of the Cell Medium 12589049
1993 For IκBα/MAD-3, an acidic region plus six ankyrin repeats are sufficient and required for Rel protein interaction and inhibition of DNA binding; both IκBα and p105/pdI form heterotrimeric complexes with Rel factors; deletion of only three amino acids in the first ankyrin repeat converts p105 subunit specificity into that of IκBα/MAD-3, demonstrating modular combinatorial specificity of the ankyrin repeat domain. Domain deletion analysis, native gel analysis, protein cross-linking, DNA-binding inhibition assays The EMBO Journal High 8334994
2022 In glioblastoma cells, high glucose promotes HK2 dissociation from mitochondria and its subsequent direct binding and phosphorylation of IκBα at T291; this phosphorylation increases interaction between IκBα and μ-calpain, leading to μ-calpain-mediated IκBα degradation and NF-κB-dependent PD-L1 upregulation; IκBα T291A substitution blocks this pathway. Co-immunoprecipitation, in vitro kinase assay, T291A mutant IκBα expression in glioblastoma cells, HK inhibitor treatment, in vivo tumor models Cell Metabolism High 36007522
2020 TRIM22 (an E3 ubiquitin ligase) binds IκBα and accelerates its degradation by inducing K48-linked polyubiquitination; TRIM22 also forms a complex with IKKγ/NEMO promoting K63-linked ubiquitination of NEMO, leading to phosphorylation of IKKα/β and subsequently of IκBα; TRIM22 RING-domain mutants unable to perform ubiquitination fail to promote GBM cell proliferation. Co-immunoprecipitation, RING-domain deletion and active-site (C15/18A) mutation, K48/K63 ubiquitination assays, NF-κB reporter assay Cell Death and Differentiation High 32814880
2015 GRK6 directly phosphorylates IκBα at Ser32/Ser36 in vitro and in cells following TNFα stimulation; GRK6 kinase activity is required for promotion of NF-κB signaling after TNFα; knockout of GRK6 in peritoneal macrophages markedly attenuates transcription of inflammatory genes after TNFα stimulation. In vitro kinase assay, GRK6 knockout macrophages, BRET conformational probe, NF-κB reporter Biochemical and Biophysical Research Communications Medium 25881508
2021 The DNA damage response triggers two mechanistically distinct phases of NF-κB activation: the first phase is driven by the ATM-PARP1-TRAF6-IKK cascade causing proteasomal IκBα destruction and is terminated by IκBα re-expression; the second (senescence) phase is IKK- and proteasome-independent, driven by altered p65/RelA phosphorylation (partly via GSK3β) that causes transcriptional silencing of the NFKBIA gene. RNA-sequencing, pharmacological IKK and proteasome inhibition, GSK3β inhibition, in vivo and in vitro DNA damage models The EMBO Journal High 33459422
2015 Nuclear import and export of free IκBα, nuclear export of the IκBα–NF-κB complex, and the free IκBα half-life are key determinants of NF-κB negative feedback control; NF-κB-inducible expression of IκBα alone is not sufficient for effective negative feedback, as shown by computational modeling followed by biochemical and single-cell live-imaging experimental validation. Computational NF-κB signaling simulations, single-cell live imaging, biochemical assays Journal of the Royal Society Interface Medium 26311312
2014 Ribosomal protein S3 (RPS3) interacts with IκBα in resting cells; IκBα facilitates reconstitution of a p65–RPS3 complex in vitro, suggesting IκBα sequesters both p65 and RPS3 in the cytoplasm to maintain an equimolar pool for NF-κB pathway activation upon stimulation. Co-immunoprecipitation in resting HEK293 cells, in vitro binding assay between RPS3 and IκBα FEBS Letters Medium 24457201
2017 TRIM67 inhibits TNFα-triggered NF-κB activation by competitively binding β-TrCP and preventing β-TrCP-mediated IκBα ubiquitination and degradation; TRIM67 overexpression suppresses IκBα degradation and pro-inflammatory cytokine expression, while Trim67 depletion enhances TNFα responses. Co-immunoprecipitation, competition binding assay, TRIM67 overexpression/knockdown, NF-κB reporter Frontiers in Immunology Medium 35273593
2020 HDAC4 functions as a SUMO E3 ligase directly sumoylating IκBα; sumoylation of IκBα prevents its polyubiquitination and degradation because both modifications occur at Lys21; cytoplasmic localization of HDAC4 and its Cys292 are required for IκBα sumoylation; this mechanism negatively regulates NF-κB activation. SUMO E3 ligase activity assay, Lys21 mutagenesis, HDAC4 localization mutants, Cys292 mutation, ubiquitination assays Journal of Molecular Cell Biology High 32770227
2023 Fructose-1,6-bisphosphatase 1 (FBP1) acts as a protein phosphatase that directly interacts with and dephosphorylates IκBα at S32/S36 upon TNFα stimulation, thereby inhibiting NF-κB activation; the catalytic mechanism is similar to FBP1-mediated F-1,6-BP dephosphorylation with higher energetic barriers; FBP1-dependent NF-κB inactivation suppresses colorectal tumorigenesis. High-throughput screening with molecular docking, phosphoproteomic analysis, in vitro dephosphorylation assay, molecular dynamics simulations, co-immunoprecipitation, FBP1 knockdown/overexpression Cell Research High 36646759
2018 Bmi1 polycomb protein associates with the SCF ubiquitin ligase complex via its N-terminus in the cytoplasm and promotes IκBα ubiquitination via an IKKα/β phosphorylation-dependent pathway; Bmi1 deficiency inhibits NF-κB-mediated gene expression in vitro and attenuates NF-κB-mediated arthritis in vivo. Co-immunoprecipitation, Bmi1 knockout cells and mouse arthritis model, IKK inhibitor treatment Journal of Immunology Medium 30209188
2017 F-box protein FBXO32 is stabilized by genotoxic or inflammatory stress and promotes polyubiquitination and proteasomal degradation of IκBα, activating NF-κB; FBXO32 also regulates physiological IκBα levels in unstressed cells; this provides an alternative F-box protein pathway to βTRCP1 for IκBα degradation during stress. FBXO32 overexpression/knockdown, ubiquitination assay, proteasome inhibitor treatment, NF-κB reporter The International Journal of Biochemistry & Cell Biology Medium 28970077
2019 Hypoxia induces rapid, transient co-translocation of RelA and IκBα into mitochondria in a ROS-dependent and STAT3-dependent manner; inhibition of STAT3 blocks RelA and IκBα mitochondrial localization; only RelA (not IκBα) is found in the mitoplast (site of mtDNA), indicating distinct sub-mitochondrial compartmentalization. Mitochondrial fractionation including mitoplast preparation, ROS scavenging, STAT3 inhibition, immunoblotting Bioscience Reports Medium 31484794
2023 Histone demethylase KDM5B is recruited to the Nfkbia promoter in activated macrophages and mediates H3K4me3 demethylation, decreasing chromatin accessibility of the Nfkbia locus and suppressing IκBα expression, thereby enabling full NF-κB activation and pro-inflammatory cytokine production; KDM5B deficiency protected mice from collagen-induced arthritis and endotoxin shock. Genome-wide KDM5B ChIP-seq, ATAC-seq, KDM5B knockout and inhibitor treatment, mouse arthritis and endotoxin shock models Cell Death and Differentiation High 36914768
2013 Multiple UBXN family members (UBXN1, UBXN9, UBXN11) inhibit IκBα degradation by binding Cullin1 (Cul1), thereby blocking SCFβ-TrCP E3 ligase activity; UBXN1 knockdown causes prolonged IκBα degradation and enhanced NF-κB signaling; UBXN1 CRISPR knockout in mouse embryo fibroblasts phenocopies prolonged IκBα degradation. Co-immunoprecipitation with Cul1, UBXN1 knockdown/knockout (shRNA and CRISPR), NF-κB reporter, IκBα degradation assay PLoS Pathogens Medium 28152074
2023 Deubiquitinase USP39 stabilizes basal IκBα by removing K48-linked polyubiquitin chains; USP39 directly interacts with IκBα; USP39 knockdown/knockout in macrophages increases IκBα ubiquitination, enhances NF-κB-dependent pro-inflammatory cytokine expression, and sensitizes mice to LPS- or E. coli-induced sepsis. Co-immunoprecipitation, K48-linked ubiquitin-specific assay, USP39 knockdown/knockout macrophages, USP39 knockout mice, sepsis model Journal of Immunology High 36651806
2025 N4BP3 interacts with IκBα and promotes K48-linked ubiquitination of IκBα, enhancing NF-κB pathway activation; N4BP3 overexpression increases K48-linked ubiquitination of IκBα in THP-1 cells; N4BP3 knockdown in mice decreases phospho-NF-κB p65 and increases IκBα protein in DSS-induced colitis. Co-immunoprecipitation, K48-linked ubiquitination assay, N4BP3 overexpression/knockdown, DSS-induced colitis mouse model Journal of Inflammation Research Medium 40487287
2020 Intestinal epithelial cell-specific knockout of Nfkbia/IκBα in mice induces constitutive NF-κB activation causing IBD hallmarks including increased apoptosis, mucosal inflammation, crypt hyperplasia, Paneth cell depletion, and aberrant Wnt signaling; in organoids, constitutive NF-κB promotes stem-cell proliferation, Paneth cell mis-localization, and apoptosis sensitization in a cell-intrinsic manner. Tissue-specific Nfkbia knockout mouse, long-term organoid culture, histological and molecular analysis The Journal of Pathology High 32222043

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 711 9865693
1998 Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature 565 9859996
2022 Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα. Cell metabolism 330 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
1996 Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein kinase II affects intrinsic protein stability. Molecular and cellular biology 183 8657113
2008 NF-kappaB dictates the degradation pathway of IkappaBalpha. The EMBO journal 170 18401342
2007 NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases. Histology and histopathology 162 17701919
2006 Proteasome-mediated degradation of IkappaBalpha and processing of p105 in Crohn disease and ulcerative colitis. The Journal of clinical investigation 133 17124531
2020 TRIM22 activates NF-κB signaling in glioblastoma by accelerating the degradation of IκBα. Cell death and differentiation 126 32814880
2010 Molecular mechanisms of system control of NF-kappaB signaling by IkappaBalpha. Biochemistry 118 20055496
1998 Defective IkappaBalpha in Hodgkin cell lines with constitutively active NF-kappaB. Oncogene 109 9572494
2004 The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. The Journal of experimental medicine 102 15337789
2000 Signal-dependent and -independent degradation of free and NF-kappa B-bound IkappaBalpha. The Journal of biological chemistry 100 10801847
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) 91 11673497
1993 Common structural constituents confer I kappa B activity to NF-kappa B p105 and I kappa B/MAD-3. The EMBO journal 91 8334994
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
2001 Control of IkappaBalpha proteolysis by the ubiquitin-proteasome pathway. Biochimie 79 11295496
2021 Exosome-based delivery of super-repressor IκBα ameliorates kidney ischemia-reperfusion injury. Kidney international 76 34051264
2003 Basal expression of IkappaBalpha is controlled by the mammalian transcriptional repressor RBP-J (CBF1) and its activator Notch1. The Journal of biological chemistry 76 12700242
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