Affinage

Showing IKBKG — IKKG is a alias.

IKBKG

NF-kappa-B essential modulator · UniProt Q9Y6K9

Length
419 aa
Mass
48.2 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IKBKG (NEMO/IKKγ) is the essential non-catalytic regulatory subunit of the IκB kinase complex and the central scaffold that couples upstream signals to NF-κB activation (PMID:9751060, PMID:10911992). Through its N-terminal region it binds preferentially to IKKβ (and IKKα), forming a defined high-affinity 2:2 complex, and its loss completely blocks cytokine-induced NF-κB activation, causing embryonic lethality from massive hepatocyte apoptosis and phenocopying incontinentia pigmenti in heterozygous females (PMID:10911992, PMID:18266324). NEMO functions as a ubiquitin sensor: K63-linked and M1/linear polyubiquitin chains, generated by upstream E3 ligases, engage its NUB and zinc-finger domains and drive its assembly into liquid-liquid phase-separated condensates within which IKK is activated, with disease-associated NEMO mutations impairing both ubiquitin engagement and phase separation (PMID:35477005, PMID:36720498, PMID:29111346). This ubiquitin-scaffold logic operates across diverse inputs—TNF and IL-1 receptor signaling (PMID:24446482), genotoxic stress via ATM (PMID:21458669), and cytosolic nucleic-acid sensing through cGAS-STING and MAVS (PMID:28939760, PMID:29125880). NEMO activity is tuned by extensive post-translational modification, including feedback phosphorylation by IKKβ, GSK-3β, DNA-PK and Src-family kinases, K63-linked ubiquitination requiring p62/TRAF6, K48-linked degradative ubiquitination by MARCH2, and SUMOylation (PMID:11971901, PMID:23131831, PMID:27929056, PMID:31932854, PMID:24270048, PMID:32935379, PMID:31549402). Beyond transcription, NEMO carries an NF-κB-independent antiapoptotic role, restraining RIPK1 from engaging caspase-8 and thereby preventing hepatocyte death and hepatocarcinogenesis (PMID:19373245, PMID:26555174), is recruited to Parkin-marked damaged mitochondria to initiate inflammatory signaling (PMID:37683611), and co-condenses with p62 to promote autophagic clearance of protein aggregates independently of NF-κB (PMID:38114471).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1998 High

    Established that the IKK complex contains an essential regulatory subunit distinct from its catalytic kinases, defining NEMO as required for IKK/NF-κB activation.

    Evidence Antibody affinity purification of the IKK complex to homogeneity, cloning, and dominant-negative truncation mutants

    PMID:9751060

    Open questions at the time
    • Did not define how upstream signals engage the subunit
    • No structural basis for IKKβ binding
  2. 1999 Medium

    Mapped NEMO's modular architecture, assigning IKK binding to the N-terminus, self-association/RIP interaction to a central region, and NF-κB regulatory activity to the C-terminus.

    Evidence Co-IP and deletion mutagenesis with IκBα phosphorylation and NF-κB reporter readouts

    PMID:10734145 PMID:9927690

    Open questions at the time
    • Domain boundaries inferred from deletions, not structure
    • Single-lab functional readouts
  3. 2000 High

    Demonstrated in vivo that NEMO is indispensable for cytokine-induced NF-κB, linking its loss to hepatocyte apoptosis and human incontinentia pigmenti.

    Evidence Germline and conditional NEMO knockout mice with NF-κB assays and histology

    PMID:10911992

    Open questions at the time
    • Did not separate scaffold from ubiquitin-sensing functions
    • Mechanism of apoptosis protection unresolved at this stage
  4. 2002 High

    Identified NEMO as a substrate of its own complex, revealing IKKβ-mediated C-terminal phosphorylation as a negative feedback control on IKK activity.

    Evidence In vitro and in vivo kinase assays with site-directed mutagenesis (S369)

    PMID:11971901

    Open questions at the time
    • Physiological kinetics of feedback not quantified
    • Other modifying kinases not yet identified
  5. 2008 High

    Defined the stoichiometry and affinity determinants of the core IKKβ-NEMO interaction, showing a 2:2 complex requiring more than the minimal NBD peptide.

    Evidence SPR, ITC, and MALS biophysical reconstitution

    PMID:18266324

    Open questions at the time
    • No full-length complex structure
    • Conformational dynamics of binding not addressed
  6. 2009 High

    Revealed NEMO's solution architecture and ubiquitin-binding behavior, showing an elongated dimer that binds linear di-ubiquitin and whose tetramerization is mutually exclusive with IKK binding.

    Evidence Hydrodynamic analysis and ITC stoichiometry measurements

    PMID:19422324

    Open questions at the time
    • Functional consequence of tetramer in cells unclear
    • Did not address longer/branched ubiquitin chains
  7. 2009 Medium

    Uncovered an NF-κB-independent survival function in which NEMO blocks RIP1-caspase-8 association at an early checkpoint.

    Evidence NEMO-deficient cells with RIP1-caspase-8 co-IP and NF-κB-independent rescue

    PMID:19373245

    Open questions at the time
    • Molecular basis of RIP1 restraint not defined
    • Single-lab finding
  8. 2010 High

    Connected NEMO to genotoxic-stress NF-κB activation through ubiquitin-dependent assembly of TAK1 and IKK complexes via ELKS.

    Evidence Cell-based co-IP, ubiquitin-binding-domain mutants, and ELKS knockdown

    PMID:20932476

    Open questions at the time
    • In vitro reconstitution of the assembly not shown
    • Quantitative ubiquitin chain requirements unresolved
  9. 2010 Medium

    Showed NEMO abundance is set by chaperone-dependent stability control, with BAG3 modulating Hsp70-NEMO interaction to protect NEMO from proteasomal degradation.

    Evidence Co-IP, siRNA knockdown, and xenograft tumor model

    PMID:20368414

    Open questions at the time
    • Direct vs indirect chaperone effect not separated
    • Single-lab finding
  10. 2011 High

    Placed NEMO at the head of a biphasic ATM-driven NF-κB program that toggles between cytokine production and apoptosis after DNA damage.

    Evidence Genetic NEMO/ATM perturbation with sequential NF-κB and RIP1 phosphorylation assays

    PMID:21458669

    Open questions at the time
    • Mechanism of NEMO nuclear involvement not yet defined here
    • Cell-type generality unclear
  11. 2012 High

    Expanded the phospho-regulatory code, identifying Src-family tyrosine phosphorylation (Y374) and vFLIP-induced S377 phosphorylation as feedback brakes on NF-κB.

    Evidence In vitro kinase assays, MS site mapping, mutagenesis, and NF-κB/cytokine readouts

    PMID:23131831

    Open questions at the time
    • Physiological stimuli engaging Src kinases on NEMO unclear
    • Crosstalk with other PTMs not addressed
  12. 2013 Medium

    Established that p62/sequestosome-1 is required for TRAF6-mediated K63 ubiquitination of NEMO downstream of IL-1β.

    Evidence Co-IP, siRNA knockdown, ubiquitination and NF-κB activation assays

    PMID:24270048

    Open questions at the time
    • Direct vs scaffolded ubiquitination not distinguished
    • Single-lab finding
  13. 2014 High

    Visualized stimulus-specific recruitment of NEMO into ubiquitin-dependent peripheral supramolecular structures, distinguishing TNF from IL-1 ubiquitin requirements.

    Evidence Live-cell and super-resolution imaging in K63/LUBAC-deficient cells

    PMID:24446482

    Open questions at the time
    • Material state of structures not defined at this stage
    • Spatial relationship to receptor not fully resolved for IL-1
  14. 2015 High

    Dissected the dual NF-κB-dependent and -independent NEMO functions that suppress RIPK1 kinase-driven hepatocyte apoptosis and hepatocarcinogenesis.

    Evidence Liver-specific conditional KO, RIPK1 kinase-dead knock-in, and triple NF-κB subunit deletion epistasis

    PMID:26555174

    Open questions at the time
    • Molecular basis of the NF-κB-independent activity not biochemically defined
    • How NEMO restrains RIPK1 kinase activity unclear
  15. 2016 Medium

    Identified GSK-3β as an N-terminal NEMO kinase whose phosphorylation stabilizes NEMO and orders TNF-α-induced NF-κB signaling.

    Evidence In vitro kinase assay, co-IP, mutagenesis, and ubiquitination assay

    PMID:27929056

    Open questions at the time
    • In vivo relevance not established
    • Single-lab finding
  16. 2017 Medium

    Positioned NEMO as a ubiquitin-sensing hub in cytosolic nucleic-acid immunity, linking cGAS-STING and MAVS to IKKβ and reciprocal TBK1 activation.

    Evidence Genetic KO epistasis with ubiquitin chain synthesis/binding and reporter assays

    PMID:28939760 PMID:29125880

    Open questions at the time
    • Identity of physiological ubiquitin ligases in each pathway not fully resolved
    • Single-lab findings
  17. 2017 Medium

    Provided a structural rationale for chain-length-selective activation, showing NEMO is autoinhibited and preferentially activated by longer M1-linked over K63-linked chains.

    Evidence SEC-SAXS with truncation-mutant ubiquitin-binding assays

    PMID:29111346

    Open questions at the time
    • Conformational model not validated by full mutagenesis
    • Atomic-resolution structure of activated state lacking
  18. 2018 Medium

    Defined a nuclear-to-cytoplasmic NEMO relay in genotoxic signaling via TRIM37 monoubiquitination at K309 driving nuclear export.

    Evidence Co-IP, K309 ubiquitination mutant, nuclear fractionation, inhibitor peptide, and xenograft

    PMID:30254148

    Open questions at the time
    • Export machinery reading the monoubiquitin mark not identified
    • Single-lab finding
  19. 2019 High

    Resolved the IKKβ-binding domain structure, revealing a dynamic closed-to-open conformational switch governing ligand engagement.

    Evidence X-ray crystallography of the unbound NEMO IKKβ-binding domain

    PMID:30814588

    Open questions at the time
    • Open state not captured structurally
    • Coupling to full-length activation untested
  20. 2019 Medium

    Added citrullination (by PAD4) and SUMOylation control (by SENP1) to the NEMO modification repertoire with disease-relevant functional consequences.

    Evidence In vitro citrullination/SUMOylation assays, SENP1 overexpression, and in vivo injury models

    PMID:30943066 PMID:31549402

    Open questions at the time
    • Modified residues and their structural effects partly undefined
    • Single-lab findings
  21. 2019 Medium

    Revealed viral subversion of NEMO via induced aggregation and selective autophagy, establishing aggrephagy of NEMO as an immune-evasion route.

    Evidence Protein aggregation and autophagy flux assays with M45 mutants and co-IP

    PMID:31844296

    Open questions at the time
    • Host adaptor recruitment hierarchy partly inferred
    • Generality beyond viral context untested
  22. 2020 Medium

    Showed DNA-PK phosphorylation of NEMO at S43 licenses its nuclear entry and shuttling for genotoxic NF-κB activation.

    Evidence S43A mutagenesis, DNA-PKcs knockdown, nuclear fractionation, and SUMOylation/NF-κB assays

    PMID:31932854

    Open questions at the time
    • Integration with ATM/TRIM37 axis not reconciled
    • Single-lab finding
  23. 2020 High

    Identified MARCH2 as an E3 ligase that degrades NEMO via K48-linked ubiquitination at K326 to dampen innate immune responses.

    Evidence Co-IP, in vitro ubiquitination, K326 mutagenesis, and MARCH2 knockout mice

    PMID:32935379

    Open questions at the time
    • Temporal trigger for late-phase MARCH2 engagement unclear
    • Substrate selectivity determinants not defined
  24. 2021 High

    Defined a negative regulator that blocks NEMO oligomerization, with N4BP1 binding the COZI domain and caspase-8 cleavage relieving inhibition during TLR signaling.

    Evidence Co-IP, domain mapping, in vitro binding, caspase-8 cleavage, and N4bp1 KO mice

    PMID:33654074

    Open questions at the time
    • Structural basis of dimerization blockade not solved
    • Breadth across TLR/receptor inputs not fully mapped
  25. 2022 High

    Unified the ubiquitin-sensing model by showing polyubiquitin chains drive NEMO liquid-liquid phase separation that is required for IKK/NF-κB activation and impaired by disease mutations.

    Evidence In vitro reconstitution with purified proteins, cell-based phase separation, and disease/domain mutant analysis

    PMID:35477005 PMID:36720498

    Open questions at the time
    • Quantitative link between condensate properties and IKK output incomplete
    • In vivo relevance of condensates not demonstrated
  26. 2022 Medium

    Demonstrated isoform-specific signal routing, showing exon 5 is required for NEMO-TBK1 association and proper type I IFN versus NF-κB partitioning.

    Evidence Patient-derived cells, NEMO-Δex5 co-IP with TBK1, and pathway-selective stimulation assays

    PMID:35289316

    Open questions at the time
    • Structural basis of exon-5-dependent TBK1 binding unknown
    • Single-lab patient-derived system
  27. 2023 High

    Extended NEMO function beyond canonical signaling to organelle damage sensing and protein quality control, via Parkin-dependent recruitment to mitochondria and p62 co-condensation for aggregate autophagy.

    Evidence Live imaging, FRAP, Parkin KO, in vitro phase transition reconstitution, and patient cell analysis

    PMID:37683611 PMID:38114471

    Open questions at the time
    • Signal that recruits NEMO to mitochondria/aggregates not fully defined
    • Relative contribution of NF-κB-independent roles in vivo unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse NEMO post-translational modifications, conformational states, and condensate properties are integrated to set quantitative IKK output across distinct receptor inputs remains unresolved.
  • No atomic structure of the activated, ubiquitin-engaged full-length complex
  • No unified quantitative model linking PTM combinations to signaling outcome
  • In vivo relevance of phase separation not directly tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
CHUKELKSIKBKBMARCH2N4BP1RIPK1SQSTM1TBK1
Complex memberships
IKK complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 IKK-gamma (NEMO) is an essential regulatory subunit of the IκB kinase complex, composed of similar amounts of IKK-alpha, IKK-beta, and two differentially processed forms of IKK-gamma. IKK-gamma interacts preferentially with IKK-beta and is required for activation of the IKK complex; a C-terminal truncation mutant that still binds IKK-beta acts as a dominant negative, blocking IKK and NF-κB activation. Purification to homogeneity by monoclonal antibody affinity, molecular cloning, dominant-negative truncation mutant assays Nature High 9751060
2000 NEMO/IKKgamma is essential for NF-κB activation by proinflammatory cytokines in vivo; complete NEMO disruption causes male embryonic lethality due to massive hepatocyte apoptosis and completely blocks NF-κB activation, phenocopying incontinentia pigmenti in heterozygous females. Germline and conditional knockout mouse models, NF-κB activation assays, histology Molecular cell High 10911992
1999 FIP-3/NEMO (identified as a 14.7K adenovirus-interacting protein) inhibits NF-κB by stabilizing IκB-α (blocking TNF-α-induced IκB-α phosphorylation and degradation) and binds RIP and NIK. Its N-terminal 119 amino acids mediate IKK-beta and IKK-alpha interactions; residues 201-300 mediate self-association and RIP interaction; and the C-terminal half mediates NF-κB inhibitory activity. Co-immunoprecipitation, deletion mutagenesis, IκB-α phosphorylation assay, NF-κB reporter assay Proceedings of the National Academy of Sciences of the United States of America Medium 9927690
2000 The N-terminal 119 amino acids of FIP3/NEMO mediate interaction with IKK-beta and IKK-alpha; the carboxy-terminal half contains the NF-κB inhibitory domain and blocks IκB-α phosphorylation/degradation; residues 201-300 constitute the self-association domain and FIP3-RIP interaction domain. Deletion mutant expression, co-immunoprecipitation, IκB-α phosphorylation assay, NF-κB reporter assay The Journal of biological chemistry Medium 10734145
2002 IKK-beta phosphorylates IKK-gamma/NEMO predominantly at serine 369 in the C-terminus (as well as sites in the central region) both in vitro and in vivo upon TNF-α and IL-1 stimulation; mutation of these C-terminal serines increases IKKgamma's ability to stimulate IKKbeta kinase activity, indicating feedback regulation. In vitro kinase assay, site-directed mutagenesis, in vivo phosphorylation assay The Journal of biological chemistry High 11971901
2003 KSHV vFLIP binds IKK-gamma/NEMO at the central CCR3/4 region (amino acids 150-272) to activate the IKK complex; in KSHV-infected PEL cells, vFLIP co-elutes with an activated IKK complex (IKKalpha, IKKbeta, IKKgamma) and associates with the chaperone Hsp90, whose inhibition by geldanamycin blocks vFLIP-induced IKK activation. Yeast two-hybrid screen, bacterial/mammalian fragment expression, co-immunoprecipitation, mass spectrometry, gel filtration chromatography, Hsp90 inhibitor assay Journal of cell science High 12890756
2009 NEMO/IKKgamma has an NF-κB-independent antiapoptotic function: it prevents RIP1 from engaging caspase-8 at an early checkpoint prior to NF-κB-mediated transcription. In NEMO-deficient cells, RIP1 associates with caspase-8, causing rapid TNF-induced apoptosis independent of NF-κB status. NEMO-deficient cell lines, co-immunoprecipitation of RIP1-caspase-8 complex, NF-κB-independent rescue experiments Cell death and differentiation Medium 19373245
2009 NEMO exists as a highly elongated dimer in solution that is in weak equilibrium with a tetrameric assembly. IKKbeta peptide binding disrupts tetramerization (mutually exclusive with IKK binding). NEMO binds linear di-ubiquitin with 1:1 stoichiometry per dimer (one di-ubiquitin per NEMO dimer), with a second weaker binding site apparent at higher concentrations. Hydrodynamic/biophysical analysis (sedimentation, gel filtration), isothermal titration calorimetry, stoichiometry determination The Biochemical journal High 19422324
2010 In the genotoxic stress pathway, ATM activates the IKK kinase TAK1 through NEMO/IKKgamma and ELKS (a protein rich in Glu/Leu/Lys/Ser). K63-linked polyubiquitination of ELKS (by XIAP/UBC13) enables ELKS association with TAK1 via TAB2/3; NEMO associates with ELKS through its ubiquitin-binding domain, assembling TAK1/TAB2/3 and NEMO/IKK complexes to activate NF-κB. Cell-based co-IP, ubiquitin-binding domain mutants, ELKS knockdown, reconstitution of complex assembly Molecular cell High 20932476
2010 BAG3 promotes survival by altering the interaction between Hsp70 and IKKgamma, increasing IKKgamma availability and protecting it from proteasome-dependent degradation, thereby increasing NF-κB activity. Co-immunoprecipitation, siRNA knockdown, xenograft tumor model Proceedings of the National Academy of Sciences of the United States of America Medium 20368414
2011 In response to extensive DNA damage, ATM drives two sequential NF-κB activation phases both requiring NEMO/IKKgamma: the first induces TNF-α-TNFR1 feedforward signaling, promoting the second phase and driving RIP1 phosphorylation; RIP1 kinase then triggers JNK3-dependent IL-8 secretion and FADD-mediated caspase-8 activation, switching on cytokine production and apoptosis. Genetic knockdown/knockout of NEMO, ATM inhibition, sequential NF-κB activation assays, RIP1 phosphorylation analysis Cell High 21458669
2012 Src family protein tyrosine kinases (Src, Fyn, Lyn, Fgr) interact with and phosphorylate IKKgamma/NEMO at tyrosine 374 (Y374); Y374F mutation abrogates this phosphorylation and increases TNF-α-induced NF-κB activity. Additionally, KSHV vFLIP expression induces phosphorylation of serine 377 (S377); S377A mutation increases and S377E decreases NF-κB activity and IL-6 production, indicating negative feedback regulation. In vitro kinase assay, site-directed mutagenesis, mass spectrometry, NF-κB reporter assay, cytokine ELISA mBio High 23131831
2013 TRAF6-mediated ubiquitination of NEMO requires the scaffold protein p62/sequestosome-1. p62 interacts with NEMO; siRNA depletion of p62 abrogates TRAF6-induced NEMO ubiquitination and severely impairs NF-κB activation following IL-1β stimulation. Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, NF-κB activation assay Molecular immunology Medium 24270048
2014 TNF and IL-1 stimulation induces rapid, transient recruitment of NEMO into punctate supramolecular structures at the cell periphery that are enriched in activated IKK and ubiquitinated NEMO, and colocalize with activated TNF receptors but not IL-1 receptors. IL-1 (but not TNF) requires K63-linked and LUBAC-generated linear ubiquitin chains to recruit NEMO into these structures. Live-cell fluorescence microscopy, super-resolution imaging, cells deficient in K63 ubiquitin or LUBAC components The Journal of cell biology High 24446482
2015 NEMO prevents hepatocarcinogenesis by inhibiting RIPK1 kinase activity-driven hepatocyte apoptosis through both NF-κB-dependent and NF-κB-independent functions. Combined RelA/c-Rel/RelB deletion did not phenocopy NEMO deficiency; knock-in of kinase-inactive RIPK1 prevented hepatocyte apoptosis and HCC; RIPK1 ablation induced TRADD-dependent apoptosis, revealing distinct kinase-dependent and scaffolding functions of RIPK1 downstream of NEMO. Conditional liver-specific KO mice, RIPK1 kinase-dead knock-in, genetic epistasis with triple NF-κB subunit deletion Cancer cell High 26555174
2016 GSK-3β directly phosphorylates NEMO at serines 8, 17, 31, and 43 within its N-terminal domain and forms a complex with wild-type NEMO; point mutations at these serines abolish GSK-3β binding and phosphorylation, leading to NEMO destabilization but augmented K63-linked polyubiquitination and increased binding to IKKα and IKKβ, while impairing ordered TNF-α-induced NF-κB signaling. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, ubiquitination assay Scientific reports Medium 27929056
2017 In the cGAS-STING pathway, cytosolic DNA activates TRIM32 and TRIM56 to synthesize ubiquitin chains that bind NEMO, which subsequently activates IKKβ (not IKKα). Activated IKKβ is required for TBK1 and NF-κB activation, and TBK1 reciprocally activates IKKβ, forming a positive feedback loop for robust cytokine production. Genetic knockouts (NEMO, IKKβ, TBK1), ubiquitin chain synthesis assays, NF-κB and IFN reporter assays Journal of immunology Medium 28939760
2017 MAVS-mediated innate immune activation is partially dependent on NEMO: TRAFs' E3 ligase activity synthesizes ubiquitin chains that bind NEMO for NF-κB activation; NEMO-activated IKKα/β then phosphorylate TBK1/IKKε, linking the NEMO-dependent ubiquitin scaffold to TBK1/IKKε activation. TRAF quadruple KO cells, NEMO-deficient cells, ubiquitin chain binding assay, phosphorylation analysis PLoS pathogens Medium 29125880
2017 Evidence for M1-linked polyubiquitin-mediated conformational change in NEMO: NEMO adopts a compact conformation (Dmax ~320 Å) rather than fully extended. A region (residues 112-150) in coiled-coil 1 inhibits di-ubiquitin binding to the CC2-LZ domain, and this auto-inhibition is overcome only by longer M1-linked (not K63-linked) polyubiquitin chains, suggesting allosteric activation. SEC-SAXS (size exclusion chromatography-small angle X-ray scattering), in vitro ubiquitin-binding assays with truncation mutants Journal of molecular biology Medium 29111346
2018 TRIM37 monoubiquitinates NEMO at K309 in the nucleus in response to genotoxic stress (ATM-phosphorylated TRIM37 translocates to the nucleus); this monoubiquitination triggers nuclear export of NEMO and subsequent IKK/NF-κB activation. The ATM/TRIM37/NEMO nuclear-to-cytoplasmic axis mediates genotoxic NF-κB activation. Co-immunoprecipitation, ubiquitination assay with K309 mutant, nuclear fractionation, cell-penetrating inhibitor peptide, in vivo xenograft Cancer research Medium 30254148
2019 The IKKβ-binding domain of NEMO forms an irregular coiled coil with a dynamic interface: the unbound structure adopts a closed conformation that partially occludes three binding hot-spots and can transition to an open state for ligand binding. X-ray crystallography of unbound NEMO IKKβ-binding domain, fusion protein engineering Scientific reports High 30814588
2019 PAD4 preferentially citrullinates IKKgamma/NEMO (over IKKα or IKKβ), and this citrullination promotes NF-κB activation via IκBα phosphorylation in renal proximal tubular cells. NEMO citrullination by PAD4 contributes to ischemia-reperfusion-induced NF-κB activation and acute kidney injury. In vitro citrullination assay with recombinant proteins, IκBα phosphorylation assay, NEMO-binding peptide inhibition, in vivo ischemia-reperfusion model American journal of physiology. Renal physiology Medium 30943066
2019 Murine cytomegalovirus M45 protein induces aggregation and selective autophagy of NEMO (and RIPK1) as an immune evasion mechanism. M45 contains an 'induced protein aggregation motif' that triggers NEMO sequestration into insoluble aggregates, followed by recruitment of VPS26B and LC3-interacting adaptor TBC1D5 to degrade aggregates by selective autophagy (aggrephagy). Protein aggregation assays, autophagy flux assays, mutant M45 analysis, co-immunoprecipitation Nature microbiology Medium 31844296
2020 DNA-PK phosphorylates NEMO at serine 43, enabling its nuclear entry (SUMOylation) and subsequent nucleocytoplasmic shuttling for NF-κB activation in response to genotoxic stress. DNA-PK knockdown or S43A point mutation blocks NEMO nuclear entry and abolishes ionizing radiation-induced NF-κB activation. Site-directed mutagenesis (S43A), shRNA knockdown of DNA-PKcs, nuclear fractionation, SUMOylation assay, NF-κB activation assay Cellular and molecular life sciences Medium 31932854
2020 MARCH2 is a novel E3 ubiquitin ligase that negatively regulates NEMO by directly interacting with NEMO during the late phase of infection and catalyzing K48-linked ubiquitination of Lys326 on NEMO, leading to its proteasomal degradation and dampening innate immune responses. Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis (K326), MARCH2 knockout mice The EMBO journal High 32935379
2021 N4BP1 inhibits TLR-dependent NF-κB activation by directly binding NEMO to attenuate NEMO-NEMO dimerization/oligomerization. The UBA-like and CUE-like domains of N4BP1 interact with the NEMO COZI domain. TRIF-activated caspase-8 cleaves N4BP1 to abolish its inhibitory effect, selectively enabling TLR4/TLR3-mediated NF-κB signaling. Co-immunoprecipitation, domain mapping, N4bp1 knockout mice, in vitro binding assay, caspase-8 cleavage assay Nature communications High 33654074
2022 Polyubiquitin chains (K63-linked or linear/M1-linked) binding to NEMO robustly induce liquid-liquid phase separation of NEMO into droplets in which IKK is activated. Both the NUB domain and zinc-finger domain of NEMO contribute to polyUb binding and phase separation. NEMO mutations associated with human immunodeficiency impair phase separation. NEMO phase separation is required for IKK and NF-κB activation. In vitro reconstitution of phase separation with purified proteins, cell-based phase separation assay, disease-associated mutant analysis, IKK activation assay Molecular cell High 35477005
2022 A NEMO isoform lacking exon 5 (NEMO-Δex5) fails to associate with TBK1, impairing TLR3/RIG-I responses but not TNF-induced NF-κB. In immune cells expressing NEMO-Δex5, the inducible IKK protein (IKKi) is stabilized by NEMO-Δex5, promoting type I IFN induction. This establishes exon 5 as required for TBK1 association and regulation of the IFN response. Patient-derived cells, co-immunoprecipitation of NEMO-Δex5 with TBK1, TLR3/RIG-I vs TNF stimulation assays, IKKi stabilization assay The Journal of clinical investigation Medium 35289316
2023 NEMO is recruited to damaged mitochondria in a Parkin-dependent manner, where it partitions into phase-separated condensates colocalizing with p62. Recruitment of NEMO to damaged mitochondria brings active phospho-IKKβ, initiating NF-κB signaling and upregulation of inflammatory cytokines. This occurs in parallel with mitophagy as a damage-sensing platform. Live-cell fluorescence imaging, FRAP, Parkin knockout validation, fractionation, IKKβ phosphorylation assay Molecular cell High 37683611
2023 NEMO promotes autophagosomal clearance of protein aggregates in an NF-κB-independent manner. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentration required for ubiquitin-dependent phase transition of p62, reshaping the aggregate surface for efficient autophagic clearance. In vitro phase separation reconstitution, patient cell analysis, co-condensation assays with p62 and ubiquitin Nature communications Medium 38114471
2023 M1-linked (linear) ubiquitin chains induce phase separation of NEMO and formation of NEMO assemblies in cells after IL-1β stimulation. Phase separation is driven by both non-covalent NEMO binding to linear ubiquitin chains and covalent linkage of M1-ubiquitin to NEMO; a pathogenic NEMO mutant defective in both binding and covalent linkage to linear ubiquitin does not undergo phase separation and is defective in IL-1β-induced NF-κB activation. In vitro phase separation assay, cell-based condensate formation, disease mutant analysis, NF-κB reporter assay Life science alliance Medium 36720498
2019 SENP1-mediated de-SUMOylation of NEMO inhibits NF-κB activation in intermittent hypoxia-challenged microglia. Intermittent hypoxia enhances NEMO SUMOylation; overexpression of SENP1 decreases NEMO SUMOylation and suppresses NF-κB activation and proinflammatory cytokine production. Co-immunoprecipitation for SUMOylation, SENP1 overexpression, NF-κB reporter assay, cytokine ELISA Journal of cellular physiology Medium 31549402
2008 High-affinity interaction between IKKβ and NEMO requires a longer C-terminal region of IKKβ beyond the minimal NBD peptide. The longer IKKβ C-terminal region forms a 2:2 stoichiometric complex with NEMO, as measured by surface plasmon resonance, ITC, and MALS. Surface plasmon resonance, isothermal titration calorimetry, multiangle light scattering Biochemistry High 18266324

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 794 9751060
2000 NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Molecular cell 367 10911992
2014 TNF and IL-1 exhibit distinct ubiquitin requirements for inducing NEMO-IKK supramolecular structures. The Journal of cell biology 356 24446482
2011 Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clinical microbiology reviews 294 21734245
2004 The FIP3-Rab11 protein complex regulates recycling endosome targeting to the cleavage furrow during late cytokinesis. Molecular biology of the cell 259 15601896
2011 NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-α feedforward signaling. Cell 233 21458669
2012 DNA damage-dependent NF-κB activation: NEMO turns nuclear signaling inside out. Immunological reviews 215 22435563
2017 NEMO-IKKβ Are Essential for IRF3 and NF-κB Activation in the cGAS-STING Pathway. Journal of immunology (Baltimore, Md. : 1950) 199 28939760
2010 Nuclear initiated NF-κB signaling: NEMO and ATM take center stage. Cell research 199 21187855
2003 KSHV vFLIP binds to IKK-gamma to activate IKK. Journal of cell science 196 12890756
2017 MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner. PLoS pathogens 181 29125880
2010 ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress. Molecular cell 171 20932476
2009 Rab11-FIP3 links the Rab11 GTPase and cytoplasmic dynein to mediate transport to the endosomal-recycling compartment. Journal of cell science 160 20026645
1999 Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis. Proceedings of the National Academy of Sciences of the United States of America 147 9927690
2010 IKK{gamma} protein is a target of BAG3 regulatory activity in human tumor growth. Proceedings of the National Academy of Sciences of the United States of America 107 20368414
2013 Molecular control of the NEMO family of ubiquitin-binding proteins. Nature reviews. Molecular cell biology 105 23989959
2004 Wnt activates the Tak1/Nemo-like kinase pathway. The Journal of biological chemistry 99 14960582
2015 NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis. Cancer cell 98 26555174
2022 Liquid phase separation of NEMO induced by polyubiquitin chains activates NF-κB. Molecular cell 94 35477005
2009 NEMO/IKKgamma regulates an early NF-kappaB-independent cell-death checkpoint during TNF signaling. Cell death and differentiation 92 19373245
2016 GSK-3β controls NF-kappaB activity via IKKγ/NEMO. Scientific reports 91 27929056
2006 Posttranslational modifications of NEMO and its partners in NF-kappaB signaling. Trends in cell biology 88 16987664
2004 Rab11-FIP3 localises to a Rab11-positive pericentrosomal compartment during interphase and to the cleavage furrow during cytokinesis. Biochemical and biophysical research communications 87 15158446
2015 EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-κB pathway can cause immunodeficiency and/or inflammation. International reviews of immunology 84 26269396
2008 Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations. Human mutation 84 18350553
2017 Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations. Blood 82 28679735
2006 Structural basis for Rab11-dependent membrane recruitment of a family of Rab11-interacting protein 3 (FIP3)/Arfophilin-1. Proceedings of the National Academy of Sciences of the United States of America 81 17030804
2000 Regulation of the NF-kappaB activation pathway by isolated domains of FIP3/IKKgamma, a component of the IkappaB-alpha kinase complex. The Journal of biological chemistry 79 10734145
2009 Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. The Journal of experimental medicine 76 19635861
2008 Sequential Cyk-4 binding to ECT2 and FIP3 regulates cleavage furrow ingression and abscission during cytokinesis. The EMBO journal 75 18511905
2023 Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling. Molecular cell 71 37683611
2007 Hepatocyte-specific IKK gamma/NEMO expression determines the degree of liver injury. Gastroenterology 71 17570222
2015 Brain endothelial TAK1 and NEMO safeguard the neurovascular unit. The Journal of experimental medicine 70 26347470
2013 Insight into IKBKG/NEMO locus: report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease. Human mutation 66 24339369
2008 Arf GTPase-activating protein ASAP1 interacts with Rab11 effector FIP3 and regulates pericentrosomal localization of transferrin receptor-positive recycling endosome. Molecular biology of the cell 65 18685082
2017 NEMO Links Nuclear Factor-κB to Human Diseases. Trends in molecular medicine 64 29128367
2012 Nemo-like kinase, a multifaceted cell signaling regulator. Cellular signalling 64 23000342
2009 Nemo-like kinase induces apoptosis and inhibits androgen receptor signaling in prostate cancer cells. The Prostate 63 19514049
2007 Rab11-FIP3 is critical for the structural integrity of the endosomal recycling compartment. Traffic (Copenhagen, Denmark) 61 17394487
2006 NEMO, NFkappaB signaling and incontinentia pigmenti. Current opinion in genetics & development 61 16647846
2019 Herpesviruses induce aggregation and selective autophagy of host signalling proteins NEMO and RIPK1 as an immune-evasion mechanism. Nature microbiology 56 31844296
2010 Rab11-FIP3 binds dynein light intermediate chain 2 and its overexpression fragments the Golgi complex. Biochemical and biophysical research communications 56 20214888
2002 Regulation of Ikappa B kinase (IKK)gamma /NEMO function by IKKbeta -mediated phosphorylation. The Journal of biological chemistry 52 11971901
2003 Nemo-like kinase induces apoptosis in DLD-1 human colon cancer cells. Biochemical and biophysical research communications 51 12901858
2015 The Arf and Rab11 effector FIP3 acts synergistically with ASAP1 to direct Rabin8 in ciliary receptor targeting. Journal of cell science 49 25673879
2013 TRAF6-mediated ubiquitination of NEMO requires p62/sequestosome-1. Molecular immunology 49 24270048
2018 Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-IκB Kinase Interaction Directly from a Combinatorial Library. Journal of the American Chemical Society 47 30176143
2016 Rac1-Rab11-FIP3 regulatory hub coordinates vesicle traffic with actin remodeling and T-cell activation. The EMBO journal 47 27154205
2009 NEMO oligomerization and its ubiquitin-binding properties. The Biochemical journal 47 19422324
2010 Regulation of FOXO1 by TAK1-Nemo-like kinase pathway. The Journal of biological chemistry 46 20061393
2018 Rescue of recurrent deep intronic mutation underlying cell type-dependent quantitative NEMO deficiency. The Journal of clinical investigation 44 30422821
2007 Molecular characterization of Rab11-FIP3 binding to ARF GTPases. European journal of cell biology 44 17628206
2010 Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis. Gut 43 21115542
2019 Nemo-like Kinase Drives Foxp3 Stability and Is Critical for Maintenance of Immune Tolerance by Regulatory T Cells. Cell reports 42 30917315
2021 N4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization. Nature communications 41 33654074
2009 Rab11-FIP3 is a Rab11-binding protein that regulates breast cancer cell motility by modulating the actin cytoskeleton. European journal of cell biology 41 19327867
2018 Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation. PLoS biology 39 29889904
2014 Nemo-like kinase (NLK) inhibits the progression of NSCLC via negatively modulating WNT signaling pathway. Journal of cellular biochemistry 39 23904219
2014 Nemo-like kinase is critical for p53 stabilization and function in response to DNA damage. Cell death and differentiation 39 24926618
2022 Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype. The Journal of clinical investigation 37 35289316
2018 An ATM/TRIM37/NEMO Axis Counteracts Genotoxicity by Activating Nuclear-to-Cytoplasmic NF-κB Signaling. Cancer research 36 30254148
2016 ADP Ribosylation Factor 6 Regulates Neuronal Migration in the Developing Cerebral Cortex through FIP3/Arfophilin-1-dependent Endosomal Trafficking of N-cadherin. eNeuro 36 27622210
2020 Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics. Nature communications 34 32286300
2021 A kinome screen reveals that Nemo-like kinase is a key suppressor of hepatic gluconeogenesis. Cell metabolism 33 33951476
2020 Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2. The EMBO journal 33 32935379
2011 Distinct roles of Rab11 and Arf6 in the regulation of Rab11-FIP3/arfophilin-1 localization in mitotic cells. Genes to cells : devoted to molecular & cellular mechanisms 33 21790911
2023 Linear ubiquitination induces NEMO phase separation to activate NF-κB signaling. Life science alliance 32 36720498
2009 Nemo-like kinase is involved in NGF-induced neurite outgrowth via phosphorylating MAP1B and paxillin. Journal of neurochemistry 32 19840224
2011 Nemo kinase phosphorylates β-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin-β-catenin. Nature structural & molecular biology 31 21552260
2010 Clinical and biological significance of nemo-like kinase expression in glioma. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 31 21177110
2023 NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62. Nature communications 30 38114471
2010 Protein-protein interactions involving IKKgamma (NEMO) that promote the activation of NF-kappaB. Journal of cellular physiology 30 20301198
2010 The zinc finger domain of IKKγ (NEMO) protein in health and disease. Journal of cellular and molecular medicine 29 20345847
2017 Evidence for M1-Linked Polyubiquitin-Mediated Conformational Change in NEMO. Journal of molecular biology 28 29111346
2010 Homodimerization of Nemo-like kinase is essential for activation and nuclear localization. Molecular biology of the cell 27 21118996
2020 NF-κB inhibitor, NEMO-binding domain peptide attenuates intervertebral disc degeneration. The spine journal : official journal of the North American Spine Society 25 32413485
2020 DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation. Cellular and molecular life sciences : CMLS 24 31932854
2017 Rab11-FIP3 Regulation of Lck Endosomal Traffic Controls TCR Signal Transduction. Journal of immunology (Baltimore, Md. : 1950) 24 28235866
2021 ATM/NEMO signaling modulates the expression of PD-L1 following docetaxel chemotherapy in prostate cancer. Journal for immunotherapy of cancer 23 34301812
2016 Epithelial NEMO/IKKγ limits fibrosis and promotes regeneration during pancreatitis. Gut 23 27464707
2015 Nemo like kinase negatively regulates NF-κB activation and coelomocytes apoptosis in Apostichopus japonicus. Developmental and comparative immunology 23 26363086
2010 A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha. Proceedings of the National Academy of Sciences of the United States of America 23 20133626
2008 NEMO shuttle: a link between DNA damage and NF-kappaB activation in progeroid syndromes? Biochemical and biophysical research communications 23 18201555
2019 The IKK-binding domain of NEMO is an irregular coiled coil with a dynamic binding interface. Scientific reports 22 30814588
2018 Nemo-like kinase (NLK) primes colorectal cancer progression by releasing the E2F1 complex from HDAC1. Cancer letters 22 29803790
2024 Dual regulation of NEMO by Nrf2 and miR-125a inhibits ferroptosis and protects liver from endoplasmic reticulum stress-induced injury. Theranostics 21 38505605
2022 TREM-1 induces pyroptosis in cardiomyocytes by activating NLRP3 inflammasome through the SMC4/NEMO pathway. The FEBS journal 20 36181338
2019 Peptidyl arginine deiminase-4 exacerbates ischemic AKI by finding NEMO. American journal of physiology. Renal physiology 20 30943066
2014 Expression of Nemo-like kinase after spinal cord injury in rats. Journal of molecular neuroscience : MN 20 24395089
2010 Proteins that bind to IKKgamma (NEMO) and down-regulate the activation of NF-kappaB. Biochemical and biophysical research communications 20 20457134
2008 High-affinity interaction between IKKbeta and NEMO. Biochemistry 20 18266324
2015 The emerging role of Nemo-like kinase (NLK) in the regulation of cancers. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 19 26427665
2019 SENP1-mediated NEMO de-SUMOylation inhibits intermittent hypoxia induced inflammatory response of microglia in vitro. Journal of cellular physiology 18 31549402
2010 Nemo-like kinase (NLK) expression in osteoblastic cells and suppression of osteoblastic differentiation. Experimental cell research 18 20116374
2005 Purification and functional properties of Rab11-FIP3. Methods in enzymology 18 16473615
2021 The phosphorylation of the Smad2/3 linker region by nemo-like kinase regulates TGF-β signaling. The Journal of biological chemistry 17 33676893
2015 Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy. eLife 17 26308581
2020 Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies. International journal of molecular sciences 16 33276680
2013 A nonsense mutation in the IKBKG gene in mares with incontinentia pigmenti. PloS one 16 24324710
2012 Novel Phosphorylations of IKKγ/NEMO. mBio 16 23131831

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