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MGP003966

UniProt Annotations

Entry Information
Gene Nameinhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon
Protein EntryIKKE_HUMAN
UniProt IDQ14164
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; IsoId=Q14164-1; Sequence=Displayed; Name=2; IsoId=Q14164-2; Sequence=VSP_044305;
Catalytic ActivityATP + [I-kappa-B protein] = ADP + [I-kappa-B phosphoprotein].
FunctionSerine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG- I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Phosphorylates AKT1. {ECO:0000269|PubMed:17568778, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:19153231, ECO:0000269|PubMed:20188669, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:22532683, ECO:0000269|PubMed:23453969, ECO:0000269|PubMed:23478265}.
InductionInduced by lipopolysaccharide (LPS) and TNFA. {ECO:0000269|PubMed:23453969}.
InteractionK7Y1A2:- (xeno); NbExp=2; IntAct=EBI-307369, EBI-8788634; P27958:- (xeno); NbExp=2; IntAct=EBI-307369, EBI-6919131; Q16543:CDC37; NbExp=3; IntAct=EBI-307369, EBI-295634; O00571:DDX3X; NbExp=4; IntAct=EBI-307369, EBI-353779; P08238:HSP90AB1; NbExp=2; IntAct=EBI-307369, EBI-352572; Q14653:IRF3; NbExp=2; IntAct=EBI-307369, EBI-2650369; Q7Z434:MAVS; NbExp=4; IntAct=EBI-307369, EBI-995373; Q92844:TANK; NbExp=2; IntAct=EBI-307369, EBI-356349; Q9UHD2:TBK1; NbExp=2; IntAct=EBI-307369, EBI-356402; A7MCY6:TBKBP1; NbExp=3; IntAct=EBI-307369, EBI-359969; Q05127:VP35 (xeno); NbExp=3; IntAct=EBI-307369, EBI-6148294;
PtmAutophosphorylated and phosphorylated by IKBKB/IKKB. Phosphorylation at Ser-172 is enhanced by the interaction with DDX3X. Phosphorylated at Thr-501 upon IFN activation. {ECO:0000269|PubMed:19369195, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:23478265}.
Ptm'Lys-63'-linked polyubiquitinated at Lys-30 and Lys-401 by TRAF2:BIRC2 and TRAF2:BIRC3 complexes. Ubiquitination is induced by LPS, TNFA and interleukin-1 and required for full kinase activity and KF-kappa-B pathway activation. {ECO:0000269|PubMed:23453969}.
PtmSumoylation by TOPORS upon DNA damage is required for protection of cells against DNA damage-induced cell death. Desumoylated by SENP1. {ECO:0000269|PubMed:20188669}.
Sequence CautionSequence=BAA09772.2; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305};
SimilarityBelongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationCytoplasm. Nucleus. Nucleus, PML body. Note=Targeting to PML nuclear bodies upon DNA damage is TOPORS- dependent.
SubunitHomodimer. Interacts with MAVS/IPS1. Interacts with the adapter proteins AZI2/NAP1, TANK and TBKBP1/SINTBAD. Interacts with SIKE1. Interacts with TICAM1/TRIF, IRF3 and DDX58/RIG-I; interactions are disrupted by the interaction between IKBKE and SIKE1. Interacts with TOPORS; induced by DNA damage. Interacts with CYLD. Interacts (when polyubiquitinated) with IKBKB, IKBKG and MYD88. Interacts with DDX3X; the interaction is found to be induced upon virus infection. Interacts (via Protein kinase domain) with arenavirus protein N; the interaction inhibits IKBKE kinase function. Interacts with Ebola virus protein VP35; the interaction leads to inhibition of cellular antiviral response by blocking necessary interactions between the IKBKE and MAVS/IPS as well as its substrates IRF3 and IRF7. {ECO:0000269|PubMed:14560022, ECO:0000269|PubMed:14739303, ECO:0000269|PubMed:16177806, ECO:0000269|PubMed:16281057, ECO:0000269|PubMed:17568778, ECO:0000269|PubMed:18636086, ECO:0000269|PubMed:18636090, ECO:0000269|PubMed:19153231, ECO:0000269|PubMed:20188669, ECO:0000269|PubMed:20657822, ECO:0000269|PubMed:22532683, ECO:0000269|PubMed:23453969, ECO:0000269|PubMed:23478265}.
Tissue SpecificityHighly expressed in spleen followed by thymus, peripheral blood leukocytes, pancreas, placenta. Weakly expressed in lung, kidney, prostate, ovary and colon.
Web ResourceName=SeattleSNPs; URL="http://pga.gs.washington.edu/data/ikbke/";
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