Details for: IKBKE

Gene ID: 9641

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: IKBKE

Ensembl ID: ENSG00000263528

Description: inhibitor of nuclear factor kappa B kinase subunit epsilon

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • plasmablast CL0000980
    CSI 9.75
    rCSI 7.67%
    PRS 94.79
  • CD4-positive, alpha-beta memory T cell CL0000897
    CSI 4.75
    rCSI 3.41%
    PRS 98.6
  • ciliated cell CL0000064
    CSI 4.3
    rCSI 6.96%
    PRS 88
  • central memory CD4-positive, alpha-beta T cell CL0000904
    CSI 3.3
    rCSI 1.95%
    PRS 99.19
  • CD4-positive helper T cell CL0000492
    CSI 3
    rCSI 2.27%
    PRS 98.24
  • T follicular helper cell CL0002038
    CSI 2.73
    rCSI 2.04%
    PRS 98.23
  • CD16-positive, CD56-dim natural killer cell, human CL0000939
    CSI 2.59
    rCSI 1.73%
    PRS 97.13
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 2.43
    rCSI 1.87%
    PRS 95.78
  • club cell CL0000158
    CSI 1.88
    rCSI 2.75%
    PRS 89.82
  • intermediate monocyte CL0002393
    CSI 1.65
    rCSI 2.5%
    PRS 96.38
  • effector memory CD8-positive, alpha-beta T cell, terminally differentiated CL0001062
    CSI 0.44
    rCSI 2.19%
    PRS 98.05
  • direct pathway medium spiny neuron CL4023026
    CSI 0.25
    rCSI 6.03%
    PRS 81.08

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [IKBKE](/details-gene/9641) (Inhibitor of Nuclear Factor Kappa B Kinase Subunit Epsilon) is a protein-coding gene located on chromosome 1q32.1. It encodes a serine/threonine-protein kinase that is a critical component of the innate immune system. As a non-canonical IκB kinase (IKK), [IKBKE](/details-gene/9641) plays a central role in the activation of transcription factors such as NF-κB and interferon regulatory factors (IRFs), which are essential for mounting antiviral and inflammatory responses [Link](https://doi.org/10.1093/intimm/11.8.1357). **Overall**, its expression profile shows the highest significance in immune effector cells, particularly [plasmablasts](/details-cell/CL0000980), as well as various memory and helper T cell subsets, highlighting its key function in both innate and adaptive immunity. ## Cellular Roles and Expression Landscape The expression pattern of [IKBKE](/details-gene/9641) firmly establishes its role as a pivotal kinase in the immune system. **Overall**, its most significant expression is observed in [plasmablasts](/details-cell/CL0000980) (CSI: 9.75), suggesting a crucial function in this terminal stage of B cell differentiation responsible for high-volume antibody production. Beyond [plasmablasts](/details-cell/CL0000980), [IKBKE](/details-gene/9641) demonstrates significant expression across a spectrum of adaptive and innate immune cells. It is a notable marker in several T lymphocyte populations, including [CD4-positive, alpha-beta memory T cells](/details-cell/CL0000897) (CSI: 4.75), [central memory CD4-positive, alpha-beta T cells](/details-cell/CL0000904) (CSI: 3.30), and [CD4-positive helper T cells](/details-cell/CL0000492) (CSI: 3.00). Its importance extends to the innate immune system, with significant expression in [CD16-positive, CD56-dim natural killer cells, human](/details-cell/CL0000939) (CSI: 2.59) and monocyte subsets like [CD14-low, CD16-positive monocytes](/details-cell/CL0002396) (CSI: 2.43). Interestingly, [IKBKE](/details-gene/9641) also shows relevance in non-hematopoietic cells that form critical environmental barriers. Its expression in [ciliated cells](/details-cell/CL0000064) (CSI: 4.30) and [club cells](/details-cell/CL0000158) (CSI: 1.88) of the respiratory tract suggests it functions as a key sensor and transducer of pathogenic signals at mucosal surfaces, initiating local innate immune responses. The low significance in cell types like [direct pathway medium spiny neurons](/details-cell/CL4023026) underscores its specialized role within the immune and barrier tissue compartments. ## Pathways and Molecular Function The molecular functions and pathway involvements of [IKBKE](/details-gene/9641) are consistent with its expression profile, centering on the regulation of innate immunity and antiviral defense. As a protein serine/threonine kinase ([GO:0004674](https://www.ebi.ac.uk/QuickGO/term/GO:0004674)), its primary role is to phosphorylate and activate downstream signaling molecules. Functionally, [IKBKE](/details-gene/9641) is integral to the [positive regulation of type I interferon production](/details-go/GO:0032481) and the broader [defense response to virus](/details-go/GO:0051607). This is mediated through its direct involvement in Toll-like receptor (TLR) signaling cascades, particularly the [MyD88-independent TLR4 cascade](/details-pathway/R-HSA-166166) and the [Toll like receptor 3 (TLR3) cascade](/details-pathway/R-HSA-168164). Upon recognition of viral components, [IKBKE](/details-gene/9641), along with the related kinase TBK1, is activated to phosphorylate and induce the nuclear translocation of IRF3 and IRF7, as detailed in the '[Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)](/details-pathway/R-HSA-936964)' pathway. This kinase activity is a foundational step in establishing an antiviral state within the cell and surrounding tissue. Furthermore, [IKBKE](/details-gene/9641) contributes to inflammatory signaling through the [positive regulation of canonical NF-kappaB signal transduction](/details-go/GO:0043123), a pathway critical for the expression of pro-inflammatory cytokines, chemokines, and cell survival factors. Its involvement has been characterized in several early studies showing it is part of a novel PMA-inducible IκB kinase complex [Link](https://doi.org/10.1016/s1097-2765(00)80445-1). The extensive annotation in pathways related to viral infections, including those for SARS-CoV-1 and SARS-CoV-2 ([R-HSA-9694516](https://reactome.org/content/detail/R-HSA-9694516)), highlights its role as a key host factor targeted or modulated during viral pathogenesis [Link](https://doi.org/10.1128/jvi.01875-08). ## Research Directions The data highlights [IKBKE](/details-gene/9641) as a central hub in immune signaling, presenting several avenues for future investigation. Its diverse roles in both innate and adaptive immunity, as well as in barrier tissues, suggest complex, context-dependent functions that warrant deeper exploration. Based on its expression profile and known functions, two testable hypotheses are proposed: 1. The exceptionally high CSI score in [plasmablasts](/details-cell/CL0000980) suggests that [IKBKE](/details-gene/9641) has a specialized function in this cell type beyond canonical antiviral signaling. It may be required for the metabolic reprogramming, unfolded protein response, or survival signaling necessary to sustain massive antibody production. 2. Given its significant expression in [ciliated cells](/details-cell/CL0000064) and [club cells](/details-cell/CL0000158), [IKBKE](/details-gene/9641) likely acts as a primary sensor kinase in the respiratory epithelium, directly coupling the detection of inhaled viral pathogens to the rapid, localized induction of type I and type III interferons, thereby establishing the first line of mucosal antiviral defense. A compelling experimental approach to test the second hypothesis would be to use an *in vitro* air-liquid interface (ALI) culture of primary human bronchial epithelial cells, which differentiates to form a pseudo-stratified epithelium containing both ciliated and club cells. [IKBKE](/details-gene/9641) could be knocked down using lentiviral-delivered shRNA or silenced with CRISPR interference (CRISPRi). These cultures would then be infected apically with a respiratory virus like influenza A or SARS-CoV-2. The hypothesis would be supported if [IKBKE](/details-gene/9641)-deficient cultures exhibit significantly reduced secretion of IFN-β and IFN-λ, alongside a corresponding increase in viral replication, as measured by qPCR and plaque assays. As a kinase, [IKBKE](/details-gene/9641) is a druggable target with significant therapeutic potential. Its role in promoting inflammation and interferon responses suggests that selective **inhibition** could be beneficial in treating autoimmune diseases like systemic lupus erythematosus (SLE) or hyperinflammatory conditions where type I interferon signaling is pathologically elevated. Conversely, targeted **activation** or enhancement of [IKBKE](/details-gene/9641) activity could represent a novel strategy for cancer immunotherapy or as a host-directed antiviral prophylactic, by augmenting the innate immune response to tumors or infections.

Genular Protein ID: 410546606

Symbol: IKKE_HUMAN

Name: Inhibitor of nuclear factor kappa-B kinase subunit epsilon

UniProtKB Accession Codes:

Q14164 D3DT78 Q3B754 Q3KR43 Q5JTS6

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CORUM 1 CPTAC 2 CTD 1 ChEBI 7 ChEMBL 1 ChiTaRS 1 ComplexPortal 3 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 DrugCentral 1 EC 2 EMBL 9 Ensembl 2 ExpressionAtlas 1 GO 29 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GuidetoPHARMACOLOGY 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 12 RefSeq 4 Rhea 3 SABIO-RK 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 UniProtKB 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10421793

Title: IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases.

PubMed ID: 10421793

DOI: 10.1093/intimm/11.8.1357

PubMed ID: 10882136

Title: IKK epsilon is part of a novel PMA-inducible IkappaB kinase complex.

PubMed ID: 10882136

DOI: 10.1016/s1097-2765(00)80445-1

PubMed ID: 8590280

Title: Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1.

PubMed ID: 8590280

DOI: 10.1093/dnares/2.4.167

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 14560022

Title: Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling.

PubMed ID: 14560022

DOI: 10.1128/mcb.23.21.7780-7793.2003

PubMed ID: 14739303

Title: Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways.

PubMed ID: 14739303

DOI: 10.1074/jbc.m311629200

PubMed ID: 16281057

Title: SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways.

PubMed ID: 16281057

DOI: 10.1038/sj.emboj.7600863

PubMed ID: 16177806

Title: Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus.

PubMed ID: 16177806

DOI: 10.1038/nature04193

PubMed ID: 17568778

Title: SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK.

PubMed ID: 17568778

DOI: 10.1038/sj.emboj.7601743

PubMed ID: 17600090

Title: Negative regulation of MDA5- but not RIG-I-mediated innate antiviral signaling by the dihydroxyacetone kinase.

PubMed ID: 17600090

DOI: 10.1073/pnas.0700544104

PubMed ID: 18583960

Title: The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response.

PubMed ID: 18583960

DOI: 10.1038/emboj.2008.126

PubMed ID: 18636090

Title: Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation.

PubMed ID: 18636090

DOI: 10.1038/emboj.2008.143

PubMed ID: 18636086

Title: The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response.

PubMed ID: 18636086

DOI: 10.1038/embor.2008.136

PubMed ID: 19153231

Title: Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKepsilon and TBK-1.

PubMed ID: 19153231

DOI: 10.1128/jvi.01875-08

PubMed ID: 19369195

Title: Large-scale proteomics analysis of the human kinome.

PubMed ID: 19369195

DOI: 10.1074/mcp.m800588-mcp200

PubMed ID: 20188669

Title: SUMOylation-dependent localization of IKKepsilon in PML nuclear bodies is essential for protection against DNA-damage-triggered cell death.

PubMed ID: 20188669

DOI: 10.1016/j.molcel.2010.01.018

PubMed ID: 20657822

Title: Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion.

PubMed ID: 20657822

DOI: 10.1371/journal.ppat.1000986

PubMed ID: 21138416

Title: Novel cross-talk within the IKK family controls innate immunity.

PubMed ID: 21138416

DOI: 10.1042/bj20101701

PubMed ID: 21464307

Title: IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation.

PubMed ID: 21464307

DOI: 10.1073/pnas.1016132108

PubMed ID: 22532683

Title: Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKepsilon.

PubMed ID: 22532683

DOI: 10.1128/jvi.00187-12

PubMed ID: 23453969

Title: IKKepsilon-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex.

PubMed ID: 23453969

DOI: 10.1016/j.celrep.2013.01.031

PubMed ID: 23478265

Title: Human DEAD box helicase 3 couples IkappaB kinase epsilon to interferon regulatory factor 3 activation.

PubMed ID: 23478265

DOI: 10.1128/mcb.01603-12

PubMed ID: 24882218

Title: Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKepsilon kinase-mediated antiviral response.

PubMed ID: 24882218

DOI: 10.1016/j.immuni.2014.04.018

PubMed ID: 24706939

Title: Viral suppression of innate immunity via spatial isolation of TBK1/IKKepsilon from mitochondrial antiviral platform.

PubMed ID: 24706939

DOI: 10.1093/jmcb/mju015

PubMed ID: 26101251

Title: FKBP51 employs both scaffold and isomerase functions to promote NF-kappaB activation in melanoma.

PubMed ID: 26101251

DOI: 10.1093/nar/gkv615

PubMed ID: 27980081

Title: DDX3 directly regulates TRAF3 ubiquitination and acts as a scaffold to co-ordinate assembly of signalling complexes downstream from MAVS.

PubMed ID: 27980081

DOI: 10.1042/bcj20160956

PubMed ID: 28011935

Title: TTLL12 Inhibits the Activation of Cellular Antiviral Signaling through Interaction with VISA/MAVS.

PubMed ID: 28011935

DOI: 10.4049/jimmunol.1601194

PubMed ID: 28768861

Title: Positive and Negative Regulation of Type I Interferons by the Human T Cell Leukemia Virus Antisense Protein HBZ.

PubMed ID: 28768861

DOI: 10.1128/jvi.00853-17

PubMed ID: 29251827

Title: Quantitative Proteomics Identified TTC4 as a TBK1 Interactor and a Positive Regulator of SeV-Induced Innate Immunity.

PubMed ID: 29251827

DOI: 10.1002/pmic.201700403

PubMed ID: 31434731

Title: Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral Responses.

PubMed ID: 31434731

DOI: 10.1128/jvi.01159-19

PubMed ID: 33391252

Title: Epstein-Barr Virus Early Protein BFRF1 Suppresses IFN-beta Activity by Inhibiting the Activation of IRF3.

PubMed ID: 33391252

DOI: 10.3389/fimmu.2020.513383

PubMed ID: 17344846

Title: Patterns of somatic mutation in human cancer genomes.

PubMed ID: 17344846

DOI: 10.1038/nature05610

Sequence Information:

  • Length: 716
  • Mass: 80462
  • Checksum: 3E5FBE5840734D81
  • Sequence:
    • MQSTANYLWH TDDLLGQGAT ASVYKARNKK SGELVAVKVF NTTSYLRPRE VQVREFEVLR 
KLNHQNIVKL FAVEETGGSR QKVLVMEYCS SGSLLSVLES PENAFGLPED EFLVVLRCVV 
AGMNHLRENG IVHRDIKPGN IMRLVGEEGQ SIYKLTDFGA ARELDDDEKF VSVYGTEEYL 
HPDMYERAVL RKPQQKAFGV TVDLWSIGVT LYHAATGSLP FIPFGGPRRN KEIMYRITTE 
KPAGAIAGAQ RRENGPLEWS YTLPITCQLS LGLQSQLVPI LANILEVEQA KCWGFDQFFA 
ETSDILQRVV VHVFSLSQAV LHHIYIHAHN TIAIFQEAVH KQTSVAPRHQ EYLFEGHLCV 
LEPSVSAQHI AHTTASSPLT LFSTAIPKGL AFRDPALDVP KFVPKVDLQA DYNTAKGVLG 
AGYQALRLAR ALLDGQELMF RGLHWVMEVL QATCRRTLEV ARTSLLYLSS SLGTERFSSV 
AGTPEIQELK AAAELRSRLR TLAEVLSRCS QNITETQESL SSLNRELVKS RDQVHEDRSI 
QQIQCCLDKM NFIYKQFKKS RMRPGLGYNE EQIHKLDKVN FSHLAKRLLQ VFQEECVQKY 
QASLVTHGKR MRVVHETRNH LRLVGCSVAA CNTEAQGVQE SLSKLLEELS HQLLQDRAKG 
AQASPPPIAP YPSPTRKDLL LHMQELCEGM KLLASDLLDN NRIIERLNRV PAPPDV

Genular Protein ID: 1914938994

Symbol: A0A075B7B4_HUMAN

Name: N/A

UniProtKB Accession Codes:

A0A075B7B4

Database IDs:

ARBA 5 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID-ORCS 1 CDD 1 CTD 1 ChEBI 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 1 Ensembl 2 ExpressionAtlas 1 GO 3 Gene3D 2 GeneTree 1 HGNC 1 HOGENOM 1 InterPro 6 MassIVE 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PROSITE 3 PROSITE-ProRule 1 PeptideAtlas 2 Pfam 3 Proteomes 2 ProteomicsDB 1 RefSeq 1 SAM 1 SMART 1 SMR 1 SUPFAM 1 UCSC 1 VEuPathDB 1

Citations:

PubMed ID: 11237011

Title: Initial sequencing and analysis of the human genome.

PubMed ID: 11237011

DOI: 10.1038/35057062

PubMed ID: 15496913

Title: Finishing the euchromatic sequence of the human genome.

PubMed ID: 15496913

DOI: 10.1038/nature03001

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

Sequence Information:

  • Length: 657
  • Mass: 73750
  • Checksum: 1CAA01732C543B32
  • Sequence:
    • MQSTANYLWH TDDLLGQGAT ASVYKARNKK SGELVAVKVF NTTSYLRPRE VQVREFEVLR 
KLNHQNIVKL FAVEETGGSR QKVLVMEYCS SGSLLSVLES PENAFGLPED EFLVVLRCVV 
AGMNHLRENG IVHRDIKPGN IMRLVGEEGQ SIYKLTDFGA ARELDDDEKF VSVYGTEEYL 
HPDMYERAVL RKPQQKAFGV TVDLWSIGVT LYHAATGSLP FIPFGGPRRN KEIMYRITTE 
KPAGAIAGAQ RRENGPLEWS YTLPITCQLS LGLQSQLVPI LANILEVEQA KCWGFDQFFA 
ETSDILQRVV VHVFSLSQAV LHHIYIHAHN TIAIFQEAVH KQTSVAPRHQ EYLFEGHLCV 
LEPSVSAQHI AHTTASSPLT LFSTAIPKGL AFRDPALDVP KFVPKVDLQA DYNTAKGVLG 
AGYQALRLAR ALLDGQELMF RGLHWVMEVL QATCRRTLEV ARTSLLYLSS SLGTERFSSV 
AGTPEIQELK AAAELRSRLR TLAEVLSRCS QNITETQESL SSLNRELVKS RDQVHEDRSI 
QQIQCCLDKM NFIYKQFKKS RMRPGLGYNE EQIHKLDKVN FSHLAKRLLQ VFQEECVQKY 
QASLVTHGKR MRVVHETRNH LRLVGCSVAA CNTEAQGVQE SLSKHARALR GDEAAGI