Protein: Inhibitor of nuclear factor kappa-B kinase subunit epsilon (I-kappa-B kinase epsilon) (IKK-E) (IKK-epsilon) (IkBKE) (EC 2.7.11.10) (Inducible I kappa-B kinase) (IKK-i) (Q14164)
Organism: Homo sapiens (Human)
Function: Serine/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.
Subcellular location: Cytoplasm {ECO:0000269|PubMed:24882218}. Nucleus. Nucleus, PML body {ECO:0000269|PubMed:20188669}. Note=Targeting to PML nuclear bodies upon DNA damage is TOPORS-dependent (PubMed:20188669). Located diffusely throughout the cytoplasm but locates to punctate cytoplasmic bodies when coexpressed with TRIM6 (PubMed:24882218). {ECO:0000269|PubMed:20188669, ECO:0000269|PubMed:24882218}.
Sequence: MQSTANYLWHTDDLLGQGATASVYKARNKKSGELVAVKVFNTTSYLRPREVQVREFEVLRKLNHQNIVKLFAVEETGGSRQKVLVMEYCSSGSLLSVLESPENAFGLPEDEFLVVLRCVVAGMNHLRENGIVHRDIKPGNIMRLVGEEGQSIYKLTDFGAARELDDDEKFVSVYGTEEYLHPDMYERAVLRKPQQKAFGVTVDLWSIGVTLYHAATGSLPFIPFGGPRRNKEIMYRITTEKPAGAIAGAQRRENGPLEWSYTLPITCQLSLGLQSQLVPILANILEVEQAKCWGFDQFFAETSDILQRVVVHVFSLSQAVLHHIYIHAHNTIAIFQEAVHKQTSVAPRHQEYLFEGHLCVLEPSVSAQHIAHTTASSPLTLFSTAIPKGLAFRDPALDVPKFVPKVDLQADYNTAKGVLGAGYQALRLARALLDGQELMFRGLHWVMEVLQATCRRTLEVARTSLLYLSSSLGTERFSSVAGTPEIQELKAAAELRSRLRTLAEVLSRCSQNITETQESLSSLNRELVKSRDQVHEDRSIQQIQCCLDKMNFIYKQFKKSRMRPGLGYNEEQIHKLDKVNFSHLAKRLLQVFQEECVQKYQASLVTHGKRMRVVHETRNHLRLVGCSVAACNTEAQGVQESLSKLLEELSHQLLQDRAKGAQASPPPIAPYPSPTRKDLLLHMQELCEGMKLLASDLLDNNRIIERLNRVPAPPDV
InterPro domains: - IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [9-300]
- IPR051180: Inhibitor of nuclear factor kappa-B kinase (family) [1-699]
- IPR041309: TANK-binding kinase 1, coiled-coil domain 1 (domain) [400-645]
- IPR041087: TANK binding kinase 1, ubiquitin-like domain (domain) [308-392]
- IPR017441: Protein kinase, ATP binding site (binding_site) [15-38]
- IPR000719: Protein kinase domain (domain) [9-315]
Interaction partners: - NF-kappa-B essential modulator
- Interferon regulatory factor 3
- Serine/threonine-protein kinase TBK1
- TRAF family member-associated NF-kappa-B activator
- TNF receptor-associated factor 3
- TNF receptor-associated factor 6
- Mitochondrial antiviral-signaling protein
- Tumor necrosis factor receptor superfamily member 1A
- TNF receptor-associated factor 2
- Tumor necrosis factor
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0016740 (transferase activity), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0004672 (protein kinase activity), GO:0016772 (transferase activity, transferring phosphorus-containing groups), GO:0051219 (phosphoprotein binding), GO:0016773 (phosphotransferase activity, alcohol group as acceptor), GO:0004674 (protein serine/threonine kinase activity), GO:0016301 (kinase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0044419 (biological process involved in interspecies interaction between organisms), GO:0002376 (immune system process), GO:0023052 (signaling), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0009987 (cellular process), GO:0009605 (response to external stimulus), GO:0023056 (positive regulation of signaling), GO:0048584 (positive regulation of response to stimulus), GO:0019222 (regulation of metabolic process), GO:0006955 (immune response), GO:0051240 (positive regulation of multicellular organismal process), GO:0006807 (nitrogen compound metabolic process), GO:0051239 (regulation of multicellular organismal process), GO:0071704 (organic substance metabolic process), GO:0044237 (cellular metabolic process), GO:0009607 (response to biotic stimulus), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0009893 (positive regulation of metabolic process), GO:0051716 (cellular response to stimulus), GO:0023051 (regulation of signaling), GO:0006950 (response to stress), GO:0051707 (response to other organism), GO:0007154 (cell communication), GO:0007165 (signal transduction), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:0009967 (positive regulation of signal transduction), GO:1901564 (organonitrogen compound metabolic process), GO:0043207 (response to external biotic stimulus), GO:0035556 (intracellular signal transduction), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0019538 (protein metabolic process), GO:0009966 (regulation of signal transduction), GO:0006952 (defense response), GO:0060255 (regulation of macromolecule metabolic process), GO:0001817 (regulation of cytokine production), GO:0043170 (macromolecule metabolic process), GO:0045087 (innate immune response), GO:0009891 (positive regulation of biosynthetic process), GO:0098542 (defense response to other organism), GO:0006793 (phosphorus metabolic process), GO:0009894 (regulation of catabolic process), GO:0010646 (regulation of cell communication), GO:0031325 (positive regulation of cellular metabolic process), GO:0009889 (regulation of biosynthetic process), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0010647 (positive regulation of cell communication), GO:0031323 (regulation of cellular metabolic process), GO:0001819 (positive regulation of cytokine production), GO:0080090 (regulation of primary metabolic process), GO:0009615 (response to virus), GO:0009896 (positive regulation of catabolic process), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0010506 (regulation of autophagy), GO:0010628 (positive regulation of gene expression), GO:0006796 (phosphate-containing compound metabolic process), GO:0010468 (regulation of gene expression), GO:0032479 (regulation of type I interferon production), GO:0036211 (protein modification process), GO:0010557 (positive regulation of macromolecule biosynthetic process), GO:0045935 (positive regulation of nucleobase-containing compound metabolic process), GO:0051254 (positive regulation of RNA metabolic process), GO:0043412 (macromolecule modification), GO:0006954 (inflammatory response), GO:0010508 (positive regulation of autophagy), GO:0032481 (positive regulation of type I interferon production), GO:0031326 (regulation of cellular biosynthetic process), GO:0007249 (I-kappaB kinase/NF-kappaB signaling), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:1902533 (positive regulation of intracellular signal transduction), GO:0031331 (positive regulation of cellular catabolic process), GO:0051252 (regulation of RNA metabolic process), GO:0031329 (regulation of cellular catabolic process), GO:1902531 (regulation of intracellular signal transduction), GO:0031328 (positive regulation of cellular biosynthetic process), GO:0032727 (positive regulation of interferon-alpha production), GO:0016241 (regulation of macroautophagy), GO:0032647 (regulation of interferon-alpha production), GO:0032648 (regulation of interferon-beta production), GO:2001141 (regulation of RNA biosynthetic process), GO:0006468 (protein phosphorylation), GO:0006355 (regulation of DNA-templated transcription), GO:0018193 (peptidyl-amino acid modification), GO:0016310 (phosphorylation), GO:0043122 (regulation of I-kappaB kinase/NF-kappaB signaling), GO:1902680 (positive regulation of RNA biosynthetic process), GO:0043123 (positive regulation of I-kappaB kinase/NF-kappaB signaling), GO:0032728 (positive regulation of interferon-beta production), GO:0016239 (positive regulation of macroautophagy), GO:0006357 (regulation of transcription by RNA polymerase II), GO:0045893 (positive regulation of DNA-templated transcription), GO:1903508 (positive regulation of nucleic acid-templated transcription), GO:0018210 (peptidyl-threonine modification), GO:1903506 (regulation of nucleic acid-templated transcription), GO:0018105 (peptidyl-serine phosphorylation), GO:0018107 (peptidyl-threonine phosphorylation), GO:0018209 (peptidyl-serine modification), GO:0045944 (positive regulation of transcription by RNA polymerase II)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005829 (cytosol), GO:0005737 (cytoplasm), GO:0031974 (membrane-enclosed lumen), GO:0005654 (nucleoplasm), GO:0043233 (organelle lumen), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle), GO:0070013 (intracellular organelle lumen), GO:0031981 (nuclear lumen), GO:0005634 (nucleus)