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) (Q9R0T8)
Organism: Mus musculus (Mouse)
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:0000250|UniProtKB:Q14164}. Nucleus {ECO:0000250|UniProtKB:Q14164}. Nucleus, PML body {ECO:0000250|UniProtKB:Q14164}. Note=Targeting to PML nuclear bodies upon DNA damage is TOPORS-dependent. Located diffusely throughout the cytoplasm but locates to punctate cytoplasmic bodies when coexpressed with TRIM6. {ECO:0000250|UniProtKB:Q14164}.
Sequence: MQSTTNYLWHTDDLLGQGATASVYKARNKKSGEVVAVKVFNSASYRRPPEVQVREFEVLRRLNHQNIVKLFAVEETGGSRQKVLIMEYCSSGSLLSVLEDPENTFGLSEEEFLVVLRCVVAGMNHLRENGIVHRDIKPGNIMRLVGEEGQSIYKLSDFGAARKLDDDEKFVSVYGTEEYLHPDMYERAVLRKPQQKAFGVTVDLWSIGVTLYHAATGSLPFIPFGGPRRNKEIMYRITTEKPAGAISGTQKQENGPLEWSYSLPITCRLSMGLQNQLVPILANILEVEEDKCWGFDQFFAETSDILQRTVIHVFSLPQAVLHHVYIHAHNTIAIFLEAVYEQTNVTPKHQEYLFEGHPCVLEPSLSAQHIAHTAASSPLTLFSMSSDTPKGLAFRDPALDVPKFVPKVDLQADYSTAKGVLGAGYQALWLARVLLDGQALMLRGLHWVLEVLQDTCQQTLEVTRTALLYLSSSLGTERFSSGAGMPDVQERKEATELRTRLQTLSEILSKCSHNVTETQRSLSCLGEELLKNRDQIHEDNKSIQKIQCCLDKMHFIYKQFKKSRMRPGLSYNEEQIHKLDKVNFSHLAKRLLQVFQEECVQTYQVSLVTHGKRMRQVQRAQNHLHLIGHSVATCNSEARGAQESLNKIFDQLLLDRASEQGAEVSPQPMAPHPGPDPKDLVFHMQELCNDMKLLAFDLQDNNRLIERLHRVPSAPDV
InterPro domains: - IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [10-307]
- IPR051180: Inhibitor of nuclear factor kappa-B kinase (family) [1-709]
- IPR041309: TANK-binding kinase 1, coiled-coil domain 1 (domain) [402-648]
- IPR041087: TANK binding kinase 1, ubiquitin-like domain (domain) [308-395]
- IPR017441: Protein kinase, ATP binding site (binding_site) [15-38]
- IPR000719: Protein kinase domain (domain) [9-315]
Interaction partners: - Serine/threonine-protein kinase TBK1
- TRAF family member-associated NF-kappa-B activator
- Mitochondrial antiviral-signaling protein
- TNF receptor-associated factor 3
- Interferon regulatory factor 3
- NF-kappa-B essential modulator
- TNF receptor-associated factor 6
- Tumor necrosis factor
- ATP-dependent RNA helicase DDX3X
- TNF receptor-associated factor 2
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:1901363 (heterocyclic compound binding), GO:0016740 (transferase activity), GO:0097159 (organic cyclic compound binding), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0003676 (nucleic acid binding), GO:0016772 (transferase activity, transferring phosphorus-containing groups), GO:0004672 (protein kinase activity), GO:0042802 (identical protein binding), GO:0019899 (enzyme binding), GO:0004674 (protein serine/threonine kinase activity), GO:0016301 (kinase activity), GO:0016773 (phosphotransferase activity, alcohol group as acceptor), GO:0019902 (phosphatase binding), GO:0019903 (protein phosphatase binding)
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: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:0051240 (positive regulation of multicellular organismal process), GO:0002684 (positive regulation of immune system process), GO:0006807 (nitrogen compound metabolic process), GO:0002682 (regulation of immune system 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:0023051 (regulation of signaling), GO:0006950 (response to stress), GO:0002253 (activation of immune response), GO:0051707 (response to other organism), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:0009967 (positive regulation of signal transduction), GO:0060759 (regulation of response to cytokine stimulus), GO:0032103 (positive regulation of response to external stimulus), GO:1901564 (organonitrogen compound metabolic process), GO:0043207 (response to external biotic stimulus), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0080134 (regulation of response to stress), GO:0019538 (protein metabolic process), GO:0009966 (regulation of signal transduction), GO:0006952 (defense response), GO:0060255 (regulation of macromolecule metabolic process), GO:0032101 (regulation of response to external stimulus), GO:0060760 (positive regulation of response to cytokine stimulus), GO:0001817 (regulation of cytokine production), GO:0043170 (macromolecule metabolic process), GO:0002218 (activation of innate immune response), GO:0098542 (defense response to other organism), GO:0006793 (phosphorus metabolic process), GO:0009894 (regulation of catabolic process), GO:0002831 (regulation of response to biotic stimulus), GO:0050776 (regulation of immune response), GO:0070661 (leukocyte proliferation), GO:0031325 (positive regulation of cellular metabolic process), GO:0010646 (regulation of cell communication), GO:0002833 (positive regulation of response to biotic stimulus), GO:0009617 (response to bacterium), GO:0050778 (positive regulation of immune response), GO:0031323 (regulation of cellular metabolic process), GO:0010647 (positive regulation of cell communication), GO:0001819 (positive regulation of cytokine production), GO:0031349 (positive regulation of defense response), GO:0009896 (positive regulation of catabolic process), GO:0031347 (regulation of defense response), GO:0001961 (positive regulation of cytokine-mediated signaling pathway), GO:0045089 (positive regulation of innate immune response), GO:0045088 (regulation of innate immune response), GO:0001959 (regulation of cytokine-mediated signaling pathway), GO:0010506 (regulation of autophagy), GO:0010628 (positive regulation of gene expression), GO:0006796 (phosphate-containing compound metabolic process), GO:0032943 (mononuclear cell proliferation), GO:0010468 (regulation of gene expression), GO:0032479 (regulation of type I interferon production), GO:0036211 (protein modification process), GO:0043412 (macromolecule modification), GO:0010508 (positive regulation of autophagy), GO:0032481 (positive regulation of type I interferon production), GO:0042742 (defense response to bacterium), GO:0031331 (positive regulation of cellular catabolic process), GO:0031329 (regulation of cellular catabolic process), GO:0016241 (regulation of macroautophagy), GO:0032648 (regulation of interferon-beta production), GO:0006468 (protein phosphorylation), GO:0018193 (peptidyl-amino acid modification), GO:0016310 (phosphorylation), GO:0060340 (positive regulation of type I interferon-mediated signaling pathway), GO:0060338 (regulation of type I interferon-mediated signaling pathway), GO:0032728 (positive regulation of interferon-beta production), GO:0050830 (defense response to Gram-positive bacterium), GO:0016239 (positive regulation of macroautophagy), GO:0018105 (peptidyl-serine phosphorylation), GO:0018209 (peptidyl-serine modification)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005737 (cytoplasm), GO:0005829 (cytosol), GO:0005622 (intracellular anatomical structure)