Gene Symbol: Ikbke
Description: inhibitor of kappaB kinase epsilon
Alias: AW558201, IKK-E, IKK-i, IKKepsilon, Ikki, inhibitor of nuclear factor kappa-B kinase subunit epsilon, I-kappa-B kinase epsilon, IKK-epsilon, inducible I kappa-B kinase, inducible IKappaB kinase, inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon
Species: mouse
Products:     Ikbke

Top Publications

  1. tenOever B, Ng S, Chua M, McWhirter S, Garcia Sastre A, Maniatis T. Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science. 2007;315:1274-8 pubmed
    b>IKKepsilon is an IKK (inhibitor of nuclear factor kappaBkinase)-related kinase implicated in virus induction of interferon-beta (IFNbeta)...
  2. Zhang M, Wu X, Lee A, Jin W, Chang M, Wright A, et al. Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD. J Biol Chem. 2008;283:18621-6 pubmed publisher
    The IkappaB kinase (IKK)-related kinases, IKKepsilon and TBK1, participate in the induction of type I interferons (IFNs) during viral infections...
  3. Koop A, Lepenies I, Braum O, Davarnia P, Scherer G, Fickenscher H, et al. Novel splice variants of human IKK? negatively regulate IKK?-induced IRF3 and NF-kB activation. Eur J Immunol. 2011;41:224-34 pubmed publisher
    ..Taken together, our data suggest alternative splicing as a novel regulatory mechanism suitable to shift the balance between different functions of IKK?. ..
  4. Jin J, Xiao Y, Chang J, Yu J, Hu H, Starr R, et al. The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-?B signaling. Nat Immunol. 2012;13:1101-9 pubmed publisher
    ..Our findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-?B pathway and identify a unique mechanism that controls IgA production. ..
  5. Bulek K, Liu C, Swaidani S, Wang L, Page R, Gulen M, et al. The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation. Nat Immunol. 2011;12:844-52 pubmed publisher
    ..we report that Act1, the key adaptor for the IL-17 receptor (IL-7R), formed a complex with the inducible kinase IKKi after stimulation with IL-17...
  6. Möser C, Kynast K, Baatz K, Russe O, Ferreirós N, Costiuk H, et al. The protein kinase IKK? is a potential target for the treatment of inflammatory hyperalgesia. J Immunol. 2011;187:2617-25 pubmed publisher
    ..Therefore, we concluded that IKK? modulates inflammatory nociceptive sensitivity by activation of NF-?B-dependent gene transcription and may be useful as a therapeutic target in the treatment of inflammatory pain. ..
  7. Xie X, Zhang D, Zhao B, Lu M, You M, Condorelli G, et al. IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A. 2011;108:6474-9 pubmed publisher
    ..Our observations suggest a physiological function of IKK?/TBK1 in AKT regulation and a possible mechanism of IKK?/TBK1 in oncogenesis by activating AKT. ..
  8. Guo B, Cheng G. Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK. J Biol Chem. 2007;282:11817-26 pubmed
    ..adaptor inducing interferon-beta), and TRAF3 and downstream mediators TANK-binding kinase 1, inducible IkappaB kinase, and interferon regulatory factor 3...
  9. Hemmi H, Takeuchi O, Sato S, Yamamoto M, Kaisho T, Sanjo H, et al. The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J Exp Med. 2004;199:1641-50 pubmed
    ..Recently, two IkappaB kinase (IKK)-related kinases, inducible IkappaB kinase (IKK-i) and TANK-binding kinase 1 (TBK1), were suggested to act as IRF-3 kinases and be involved in IFN-..

More Information


  1. Shimada T, Kawai T, Takeda K, Matsumoto M, Inoue J, Tatsumi Y, et al. IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases. Int Immunol. 1999;11:1357-62 pubmed
    ..These results suggest that IKK-i is an inducible IkappaB kinase which may play a special role in the immune response.
  2. Scheja L, Heese B, Seedorf K. Beneficial effects of IKK?-deficiency on body weight and insulin sensitivity are lost in high fat diet-induced obesity in mice. Biochem Biophys Res Commun. 2011;407:288-94 pubmed publisher
  3. Kravchenko V, Mathison J, Schwamborn K, Mercurio F, Ulevitch R. IKKi/IKKepsilon plays a key role in integrating signals induced by pro-inflammatory stimuli. J Biol Chem. 2003;278:26612-9 pubmed
    We report that the product of the inducible gene encoding the kinase known as IKKi/IKKepsilon (IKKi) is required for expression of a group of genes up-regulated by pro-inflammatory stimuli such as bacterial endotoxin (lipopolysaccharide (..
  4. Chiang S, Bazuine M, Lumeng C, Geletka L, Mowers J, White N, et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell. 2009;138:961-75 pubmed publisher
    ..increase NF-kappaB activation in mice, which leads to a sustained elevation in level of IkappaB kinase epsilon (IKKepsilon) in liver, adipocytes, and adipose tissue macrophages...
  5. Ikeda F, Hecker C, Rozenknop A, Nordmeier R, Rogov V, Hofmann K, et al. Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes. EMBO J. 2007;26:3451-62 pubmed
    ..We propose that the ULD is a regulatory component of the TBK1/IKK-i kinases involved in the control of the kinase activation, substrate presentation and downstream signaling pathways. ..
  6. Sweeney S, Hammaker D, Boyle D, Firestein G. Regulation of c-Jun phosphorylation by the I kappa B kinase-epsilon complex in fibroblast-like synoviocytes. J Immunol. 2005;174:6424-30 pubmed
    ..The IkappaB kinase (IKK)-related kinase, IKKepsilon/IKKi, which plays a pivotal role in regulating antiviral gene transcription, is constitutively expressed by ..
  7. Rajsbaum R, Versteeg G, Schmid S, Maestre A, Belicha Villanueva A, Martínez Romero C, et al. Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKK? kinase-mediated antiviral response. Immunity. 2014;40:880-95 pubmed publisher
    ..Our work attributes a previously unrecognized activating role of K48-linked unanchored polyubiquitin chains in kinase activation and identifies the UbE2K-TRIM6-ubiquitin axis as critical for IFN signaling and antiviral response. ..
  8. Kuriakose T, Man S, Subbarao Malireddi R, Karki R, Kesavardhana S, Place D, et al. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci Immunol. 2016;1:aag2045 pubmed publisher
    ..Overall, these findings indicate that ZBP1 is an innate immune sensor of IAV and highlight its importance in the pathogenesis of IAV infection. ..
  9. Moreno R, Sobotzik J, Schultz C, Schmitz M. Specification of the NF-kappaB transcriptional response by p65 phosphorylation and TNF-induced nuclear translocation of IKK epsilon. Nucleic Acids Res. 2010;38:6029-44 pubmed publisher
    ..In the nucleus, the kinase contributes to the expression of a subset of NF-?B-regulated genes, thus revealing a novel role of IKK? for the control of nuclear NF-?B activity. ..
  10. Wang S, Xie F, Chu F, Zhang Z, Yang B, Dai T, et al. YAP antagonizes innate antiviral immunity and is targeted for lysosomal degradation through IKK?-mediated phosphorylation. Nat Immunol. 2017;18:733-743 pubmed publisher
  11. Smith H, Liu X, Dai L, Goh E, Chan A, Xi J, et al. The role of TBK1 and IKKε in the expression and activation of Pellino 1. Biochem J. 2011;434:537-48 pubmed publisher
    ..Thus IKKε/TBK1 mediate the activation of Pellino 1's E3 ligase activity, as well as inducing the transcription of its gene and protein expression in response to TLR3 and TLR4 agonists. ..
  12. Rajurkar M, Dang K, Fernández Barrena M, Liu X, Fernandez Zapico M, Lewis B, et al. IKBKE Is Required during KRAS-Induced Pancreatic Tumorigenesis. Cancer Res. 2017;77:320-329 pubmed publisher
    ..Here, we show that the noncanonical IκB-related kinase, IKBKE, is a critical oncogenic effector during KRAS-induced pancreatic transformation...
  13. Yu J, Zhou X, Chang M, Nakaya M, Chang J, Xiao Y, et al. Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nat Commun. 2015;6:6074 pubmed publisher
    ..Treatment of mice with a small-molecule inhibitor of TBK1 inhibits EAE induction. These results suggest a role for TBK1 in regulating T-cell migration and establish TBK1 as a regulator of the AKT-mTORC1 signalling axis. ..
  14. Alves B, Tsui R, Almaden J, Shokhirev M, Davis Turak J, Fujimoto J, et al. I?B? is a key regulator of B cell expansion by providing negative feedback on cRel and RelA in a stimulus-specific manner. J Immunol. 2014;192:3121-32 pubmed publisher
    ..This study illustrates the importance of kinetic considerations in understanding the functional specificity of negative-feedback regulators. ..
  15. Bruni D, Sebastia J, Dunne S, Schröder M, Butler M. A novel IRAK1-IKK? signaling axis limits the activation of TAK1-IKK? downstream of TLR3. J Immunol. 2013;190:2844-56 pubmed publisher
  16. Ng S, Friedman B, Schmid S, Gertz J, Myers R, tenOever B, et al. I?B kinase epsilon (IKK(epsilon)) regulates the balance between type I and type II interferon responses. Proc Natl Acad Sci U S A. 2011;108:21170-5 pubmed publisher
    ..We conclude that IKK? plays a critical role in regulating the balance between the IFN-I and IFN-II signaling pathways. ..
  17. Gulen M, Bulek K, Xiao H, Yu M, Gao J, Sun L, et al. Inactivation of the enzyme GSK3? by the kinase IKKi promotes AKT-mTOR signaling pathway that mediates interleukin-1-induced Th17 cell maintenance. Immunity. 2012;37:800-12 pubmed publisher
    ..Via biochemical and genetic approaches, the kinases IKKi and GSK3? were identified as the critical intermediate signaling components for IL-1-induced AKT activation, which ..
  18. Savinova O, Hoffmann A, Ghosh G. The Nfkb1 and Nfkb2 proteins p105 and p100 function as the core of high-molecular-weight heterogeneous complexes. Mol Cell. 2009;34:591-602 pubmed publisher
    ..Our biochemical evidence suggests an assembly pathway in which kinetic mechanisms control NF-kappaB dimer formation via processing and assembly of large complexes that contain IkappaB activities. ..
  19. Göktuna S, Shostak K, Chau T, Heukamp L, Hennuy B, Duong H, et al. The Prosurvival IKK-Related Kinase IKKε Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine. Cancer Res. 2016;76:2587-99 pubmed publisher
    ..Cancer Res; 76(9); 2587-99. ©2016 AACR. ..
  20. Wang Y, Lu X, Zhu L, Shen Y, Chengedza S, Feng H, et al. IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis. Proc Natl Acad Sci U S A. 2013;110:11139-44 pubmed publisher
    ..Collectively, our findings uncover a critical IKK? in promoting NF-?B activation and tumorigenesis induced by a viral GPCR. ..
  21. Dai J, Shen D, Bian Z, Zhou H, Gan H, Zong J, et al. IKKi deficiency promotes pressure overload-induced cardiac hypertrophy and fibrosis. PLoS ONE. 2013;8:e53412 pubmed publisher
    The inducible I?B kinase (IKKi/IKK?) is a recently described serine-threonine IKK-related kinase. Previous studies have reported the role of IKKi in infectious diseases and cancer...
  22. Ishii K, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol. 2006;7:40-8 pubmed
    ..the promoter of the gene encoding interferon-beta through a signaling pathway that required the kinases TBK1 and IKKi, whereas there was substantial activation of transcription factor NF-kappaB independent of both TBK and IKKi...
  23. Watanabe T, Asano N, Fichtner Feigl S, Gorelick P, Tsuji Y, Matsumoto Y, et al. NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Invest. 2010;120:1645-62 pubmed publisher
    ..This in turn led to activation of TANK-binding kinase 1 (TBK1) and IkappaB kinase epsilon (IKKepsilon) and the subsequent activation of IFN regulatory factor 7 (IRF7)...
  24. Bibeau Poirier A, Gravel S, Clément J, Rolland S, Rodier G, Coulombe P, et al. Involvement of the IkappaB kinase (IKK)-related kinases tank-binding kinase 1/IKKi and cullin-based ubiquitin ligases in IFN regulatory factor-3 degradation. J Immunol. 2006;177:5059-67 pubmed
  25. Matsui K, Kumagai Y, Kato H, Sato S, Kawagoe T, Uematsu S, et al. Cutting edge: Role of TANK-binding kinase 1 and inducible IkappaB kinase in IFN responses against viruses in innate immune cells. J Immunol. 2006;177:5785-9 pubmed
    TANK-binding kinase 1 (TBK1) and inducible IkappaB kinase (IKK-i) are involved in the activation of transcription factors inducing the production of type I IFNs...
  26. Xu J, Zhou L, Ji L, Chen F, Fortmann K, Zhang K, et al. The REGγ-proteasome forms a regulatory circuit with IκBɛ and NFκB in experimental colitis. Nat Commun. 2016;7:10761 pubmed publisher
    ..In sum, this study identifies REGγ-mediated control of IκBɛ as a molecular mechanism that contributes to NFκB activation and promotes bowel inflammation and associated tumour formation in response to chronic injury. ..
  27. Maitra U, Gan L, Chang S, Li L. Low-dose endotoxin induces inflammation by selectively removing nuclear receptors and activating CCAAT/enhancer-binding protein ?. J Immunol. 2011;186:4467-73 pubmed publisher
    ..Taken together, these data reveal a distinct pathway preferentially used by low-dose endotoxin in initiating low-grade inflammation. ..
  28. Ishii K, Kawagoe T, Koyama S, Matsui K, Kumar H, Kawai T, et al. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature. 2008;451:725-9 pubmed publisher
    ..These data suggest that TBK1 is a key signalling molecule for DNA-vaccine-induced immunogenicity, by differentially controlling DNA-activated innate immune signalling through haematopoietic and non-haematopoietic cells. ..
  29. Sweeney S, Mo L, Firestein G. Antiviral gene expression in rheumatoid arthritis: role of IKKepsilon and interferon regulatory factor 3. Arthritis Rheum. 2007;56:743-52 pubmed
    ..This study was designed to investigate the role of the IKK-related kinase IKKepsilon and IFN regulatory factor 3 (IRF-3) in the activation of antiviral genes in rheumatoid arthritis (RA)...
  30. Civas A, Genin P, Morin P, Lin R, Hiscott J. Promoter organization of the interferon-A genes differentially affects virus-induced expression and responsiveness to TBK1 and IKKepsilon. J Biol Chem. 2006;281:4856-66 pubmed
    ..during viral infection by the IKK-related serine/threonine kinases TBK1 and IkappaB kinase epsilon (IKKepsilon)...
  31. Everts B, Amiel E, Huang S, Smith A, Chang C, Lam W, et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKK? supports the anabolic demands of dendritic cell activation. Nat Immunol. 2014;15:323-32 pubmed publisher
    ..In summary, we identified the rapid induction of glycolysis as an integral component of TLR signaling that is essential for the anabolic demands of the activation and function of DCs. ..
  32. Nakatsu Y, Matsuoka M, Chang T, Otsuki N, Noda M, Kimura H, et al. Functionally distinct effects of the C-terminal regions of IKK? and TBK1 on type I IFN production. PLoS ONE. 2014;9:e94999 pubmed publisher
    ..The results highlight the importance of the C-terminal region in the functional activity of IKK? in innate immune response and also the difference in activation mechanisms between IKK? and the closely related TBK1. ..
  33. Zhang J, Feng H, Zhao J, Feldman E, Chen S, Yuan W, et al. IκB Kinase ε Is an NFATc1 Kinase that Inhibits T Cell Immune Response. Cell Rep. 2016;16:405-418 pubmed publisher
    ..These results collectively show that IKKε promotes NFATc1 phosphorylation and inhibits T cell responses, identifying IKKε as a crucial negative regulator of T cell activation and a potential target for immunotherapy. ..
  34. Weissmann L, Quaresma P, Santos A, de Matos A, Pascoal V, Zanotto T, et al. IKK? is key to induction of insulin resistance in the hypothalamus, and its inhibition reverses obesity. Diabetes. 2014;63:3334-45 pubmed publisher
    b>IKK epsilon (IKK?) is induced by the activation of nuclear factor-?B (NF-?B). Whole-body IKK? knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance...
  35. Ono C, Ninomiya A, Yamamoto S, Abe T, Wen X, Fukuhara T, et al. Innate immune response induced by baculovirus attenuates transgene expression in mammalian cells. J Virol. 2014;88:2157-67 pubmed publisher
  36. Doyle S, Shirey K, McGettrick A, Kenny E, Carpenter S, Caffrey B, et al. Nuclear factor ?B2 p52 protein has a role in antiviral immunity through I?B kinase epsilon-dependent induction of Sp1 protein and interleukin 15. J Biol Chem. 2013;288:25066-75 pubmed publisher
    ..Our study identifies NF?B2 as a target for IKK? in antiviral immunity and describes, for the first time, a role for NF?B2 in the regulation of gene expression in response to viral infection. ..
  37. Sanada Y, Kumoto T, Suehiro H, Yamamoto T, Nishimura F, Kato N, et al. I?B kinase epsilon expression in adipocytes is upregulated by interaction with macrophages. Biosci Biotechnol Biochem. 2014;78:1357-62 pubmed publisher
    ..This study provides novel insight into IKK?, which is involved in adipose tissue inflammation during the development of obesity. ..
  38. Patel M, Bernard W, Milev N, Cawthorn W, Figg N, Hart D, et al. Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation. Proc Natl Acad Sci U S A. 2015;112:506-11 pubmed publisher
    ..Here, we show that inhibitor of κB kinase epsilon (IKBKE) is a novel regulator that limits chronic inflammation during metabolic disease and atherosclerosis...
  39. Cao C, Zhu Y, Chen W, Li L, Qi Y, Wang X, et al. IKK? knockout prevents high fat diet induced arterial atherosclerosis and NF-?B signaling in mice. PLoS ONE. 2013;8:e64930 pubmed publisher
  40. Guo J, Tian W, Shu S, Xin Y, Shou C, Cheng J. IKBKE phosphorylation and inhibition of FOXO3a: a mechanism of IKBKE oncogenic function. PLoS ONE. 2013;8:e63636 pubmed publisher
    ..Here we report that IKBKE regulates FOXO3a through phosphorylation of FOXO3a-Ser644...
  41. Perwitasari O, Cho H, Diamond M, Gale M. Inhibitor of ?B kinase epsilon (IKK(epsilon)), STAT1, and IFIT2 proteins define novel innate immune effector pathway against West Nile virus infection. J Biol Chem. 2011;286:44412-23 pubmed publisher
    ..Our results define an IFN-induced IKK? signaling pathway of specific STAT1 phosphorylation and IFIT2 expression that imparts innate antiviral immunity to restrict WNV infection and control viral pathogenesis. ..
  42. Cao C, Qi Y, Chen W, Zhu Y, Chen X. Effects of IKK? on oxidised low-density lipoprotein-induced injury in vascular endothelial cells. Heart Lung Circ. 2013;22:366-72 pubmed publisher
    ..IKK? might play an important role in ox-LDL-induced injury of endothelial cells. ..
  43. Mowers J, Uhm M, Reilly S, Simon J, Leto D, Chiang S, et al. Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKK? and TBK1. elife. 2013;2:e01119 pubmed publisher
    ..These studies suggest that by reducing production of cAMP in adipocytes, IKK? and TBK1 may contribute to the repression of energy expenditure during obesity. DOI: http://dx.doi.org/10.7554/eLife.01119.001. ..
  44. Cao C, Li L, Chen W, Zhu Y, Qi Y, Wang X, et al. Deficiency of IKK? inhibits inflammation and induces cardiac protection in high-fat diet-induced obesity in mice. Int J Mol Med. 2014;34:244-52 pubmed publisher
  45. Goh E, Arthur J, Cheung P, Akira S, Toth R, Cohen P. Identification of the protein kinases that activate the E3 ubiquitin ligase Pellino 1 in the innate immune system. Biochem J. 2012;441:339-46 pubmed publisher
    ..The activation of Pellino 1 provides the first direct readout for IRAK1 catalytic activity in cells. ..
  46. Farlik M, Rapp B, Marie I, Levy D, Jamieson A, Decker T. Contribution of a TANK-binding kinase 1-interferon (IFN) regulatory factor 7 pathway to IFN-?-induced gene expression. Mol Cell Biol. 2012;32:1032-43 pubmed publisher
    ..Our data thus describe a biologically relevant basal activity of TBK1 and identify IRF7 as a novel player in the IFN-? response. ..
  47. Qu F, Gao H, Zhu S, Shi P, Zhang Y, Liu Y, et al. TRAF6-dependent Act1 phosphorylation by the I?B kinase-related kinases suppresses interleukin-17-induced NF-?B activation. Mol Cell Biol. 2012;32:3925-37 pubmed publisher
    ..Recently, inducible I?B kinase (IKKi) has been shown to phosphorylate Act1 on Ser 311 to mediate IL-17-induced mRNA stability...
  48. Zhang Y, Wei G, Di Z, Zhao Q. miR-339-5p inhibits alcohol-induced brain inflammation through regulating NF-κB pathway. Biochem Biophys Res Commun. 2014;452:450-6 pubmed publisher
    ..miR-339-5p inhibited expression of these pro-inflammatory factors through the NF-κB pathway by abolishing IKK-β and IKK-ε activity. ..
  49. Chau T, Göktuna S, Rammal A, Casanova T, Duong H, Gatot J, et al. A role for APPL1 in TLR3/4-dependent TBK1 and IKKε activation in macrophages. J Immunol. 2015;194:3970-83 pubmed publisher
    ..Those signaling pathways involve the signal-induced degradation of APPL1 to prevent aberrant IRF3-dependent gene expression linked to immune diseases. ..
  50. Gracias D, Stelekati E, Hope J, Boesteanu A, Doering T, Norton J, et al. The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling. Nat Immunol. 2013;14:593-602 pubmed publisher
    ..We have thus identified a previously unknown role for miR-155 in regulating responsiveness to interferon and CD8(+) T cell responses to pathogens in vivo. ..