Inhibitor of nuclear factor kappa-B kinase subunit epsilon

Details

Name
Inhibitor of nuclear factor kappa-B kinase subunit epsilon
Synonyms
  • 2.7.11.10
  • I-kappa-B kinase epsilon
  • IKK-i
  • IKKE
  • IKKI
  • Inducible I kappa-B kinase
  • KIAA0151
Gene Name
IKBKE
Organism
Humans
Amino acid sequence
>lcl|BSEQ0051778|Inhibitor of nuclear factor kappa-B kinase subunit epsilon
MQSTANYLWHTDDLLGQGATASVYKARNKKSGELVAVKVFNTTSYLRPREVQVREFEVLR
KLNHQNIVKLFAVEETGGSRQKVLVMEYCSSGSLLSVLESPENAFGLPEDEFLVVLRCVV
AGMNHLRENGIVHRDIKPGNIMRLVGEEGQSIYKLTDFGAARELDDDEKFVSVYGTEEYL
HPDMYERAVLRKPQQKAFGVTVDLWSIGVTLYHAATGSLPFIPFGGPRRNKEIMYRITTE
KPAGAIAGAQRRENGPLEWSYTLPITCQLSLGLQSQLVPILANILEVEQAKCWGFDQFFA
ETSDILQRVVVHVFSLSQAVLHHIYIHAHNTIAIFQEAVHKQTSVAPRHQEYLFEGHLCV
LEPSVSAQHIAHTTASSPLTLFSTAIPKGLAFRDPALDVPKFVPKVDLQADYNTAKGVLG
AGYQALRLARALLDGQELMFRGLHWVMEVLQATCRRTLEVARTSLLYLSSSLGTERFSSV
AGTPEIQELKAAAELRSRLRTLAEVLSRCSQNITETQESLSSLNRELVKSRDQVHEDRSI
QQIQCCLDKMNFIYKQFKKSRMRPGLGYNEEQIHKLDKVNFSHLAKRLLQVFQEECVQKY
QASLVTHGKRMRVVHETRNHLRLVGCSVAACNTEAQGVQESLSKLLEELSHQLLQDRAKG
AQASPPPIAPYPSPTRKDLLLHMQELCEGMKLLASDLLDNNRIIERLNRVPAPPDV
Number of residues
716
Molecular Weight
80461.665
Theoretical pI
Not Available
GO Classification
Functions
ATP binding / IkappaB kinase activity / K48-linked polyubiquitin modification-dependent protein binding / NF-kappaB-inducing kinase activity / protein kinase activity / ubiquitin protein ligase binding
Processes
cellular response to virus / immune response / innate immune response / intrinsic apoptotic signaling pathway in response to DNA damage / negative regulation of type I interferon production / peptidyl-serine phosphorylation / positive regulation of I-kappaB kinase/NF-kappaB signaling / positive regulation of lipid storage / protein homooligomerization / protein phosphorylation / response to interferon-beta / response to type I interferon / TRIF-dependent toll-like receptor signaling pathway
Components
cytoplasm / cytosol / endosome membrane / mitochondrial membrane / nucleus / PML body
General 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.
Specific Function
Atp binding
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Cytoplasm
Gene sequence
>lcl|BSEQ0051779|Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE)
ATGCAGAGCACAGCCAATTACCTGTGGCACACAGATGACCTGCTGGGGCAGGGGGCCACT
GCCAGTGTGTACAAGGCCCGCAACAAGAAATCCGGAGAGCTGGTTGCTGTGAAGGTCTTC
AACACTACCAGCTACCTGCGGCCCCGCGAGGTGCAGGTGAGGGAGTTTGAGGTCCTGCGG
AAGCTGAACCACCAGAACATTGTCAAGCTCTTTGCGGTGGAGGAGACGGGCGGAAGCCGG
CAGAAGGTACTGGTGATGGAGTACTGCTCCAGTGGGAGCCTGCTGAGTGTGCTGGAGAGC
CCTGAGAATGCCTTTGGGCTGCCTGAGGATGAGTTCCTGGTGGTGCTGCGCTGTGTGGTG
GCCGGCATGAACCACCTGCGGGAGAACGGCATTGTGCATCGCGACATCAAGCCGGGGAAC
ATCATGCGCCTCGTAGGGGAGGAGGGGCAGAGCATCTACAAGCTGACAGACTTCGGCGCT
GCCCGGGAGCTGGATGATGATGAGAAGTTCGTCTCGGTCTATGGGACTGAGGAGTACCTG
CATCCCGACATGTATGAGCGGGCGGTGCTTCGAAAGCCCCAGCAAAAAGCGTTCGGGGTG
ACTGTGGATCTCTGGAGCATTGGAGTGACCTTGTACCATGCAGCCACTGGCAGCCTGCCC
TTCATCCCCTTTGGTGGGCCACGGCGGAACAAGGAGATCATGTACCGGATCACCACGGAG
AAGCCGGCTGGGGCCATTGCAGGTGCCCAGAGGCGGGAGAACGGGCCCCTGGAGTGGAGC
TACACCCTCCCCATCACCTGCCAGCTGTCACTGGGGCTGCAGAGCCAGCTGGTGCCCATC
CTGGCCAACATCCTGGAGGTGGAGCAGGCCAAGTGCTGGGGCTTCGACCAGTTCTTTGCG
GAGACCAGTGACATCCTGCAGCGAGTTGTCGTCCATGTCTTCTCCCTGTCCCAGGCAGTC
CTGCACCACATCTATATCCATGCCCACAACACGATAGCCATTTTCCAGGAGGCCGTGCAC
AAGCAGACCAGTGTGGCCCCCCGACACCAGGAGTACCTCTTTGAGGGTCACCTCTGTGTC
CTCGAGCCCAGCGTCTCAGCACAGCACATCGCCCACACGACGGCAAGCAGCCCCCTGACC
CTCTTCAGCACAGCCATCCCTAAGGGGCTGGCCTTCAGGGACCCTGCTCTGGACGTCCCC
AAGTTCGTCCCCAAAGTGGACCTGCAGGCGGATTACAACACTGCCAAGGGCGTGTTGGGC
GCCGGCTACCAGGCCCTGCGGCTGGCACGGGCCCTGCTGGATGGGCAGGAGCTAATGTTT
CGGGGGCTGCACTGGGTCATGGAGGTGCTCCAGGCCACATGCAGACGGACTCTGGAAGTG
GCAAGGACATCCCTCCTCTACCTCAGCAGCAGCCTGGGAACTGAGAGGTTCAGCAGCGTG
GCTGGAACGCCTGAGATCCAGGAACTGAAGGCGGCTGCAGAACTGAGGTCCAGGCTGCGG
ACTCTAGCGGAGGTCCTCTCCAGATGCTCCCAAAATATCACGGAGACCCAGGAGAGCCTG
AGCAGCCTGAACCGGGAGCTGGTGAAGAGCCGGGATCAGGTACATGAGGACAGAAGCATC
CAGCAGATTCAGTGCTGTTTGGACAAGATGAACTTCATCTACAAACAGTTCAAGAAGTCT
AGGATGAGGCCAGGGCTTGGCTACAACGAGGAGCAGATTCACAAGCTGGATAAGGTGAAT
TTCAGTCATTTAGCCAAAAGACTCCTGCAGGTGTTCCAGGAGGAGTGCGTGCAGAAGTAT
CAAGCGTCCTTAGTCACACACGGCAAGAGGATGAGGGTGGTGCACGAGACCAGGAACCAC
CTGCGCCTGGTTGGCTGTTCTGTGGCTGCCTGTAACACAGAAGCCCAGGGGGTCCAGGAG
AGTCTCAGCAAGCTCCTGGAAGAGCTATCTCACCAGCTCCTTCAGGACCGAGCAAAGGGG
GCTCAGGCCTCGCCGCCTCCCATAGCTCCTTACCCCAGCCCTACACGAAAGGACCTGCTT
CTCCACATGCAAGAGCTCTGCGAGGGGATGAAGCTGCTGGCATCTGACCTCCTGGACAAC
AACCGCATCATCGAACGGCTAAATAGAGTCCCAGCACCTCCTGATGTCTGA
Chromosome Location
1
Locus
1q32.1
External Identifiers
ResourceLink
UniProtKB IDQ14164
UniProtKB Entry NameIKKE_HUMAN
HGNC IDHGNC:14552
General References
  1. Shimada T, Kawai T, Takeda K, Matsumoto M, Inoue J, Tatsumi Y, Kanamaru A, Akira S: IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases. Int Immunol. 1999 Aug;11(8):1357-62. [Article]
  2. Peters RT, Liao SM, Maniatis T: IKKepsilon is part of a novel PMA-inducible IkappaB kinase complex. Mol Cell. 2000 Mar;5(3):513-22. [Article]
  3. Nagase T, Seki N, Tanaka A, Ishikawa K, Nomura N: 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. DNA Res. 1995 Aug 31;2(4):167-74, 199-210. [Article]
  4. Gregory SG, Barlow KF, McLay KE, Kaul R, Swarbreck D, Dunham A, Scott CE, Howe KL, Woodfine K, Spencer CC, Jones MC, Gillson C, Searle S, Zhou Y, Kokocinski F, McDonald L, Evans R, Phillips K, Atkinson A, Cooper R, Jones C, Hall RE, Andrews TD, Lloyd C, Ainscough R, Almeida JP, Ambrose KD, Anderson F, Andrew RW, Ashwell RI, Aubin K, Babbage AK, Bagguley CL, Bailey J, Beasley H, Bethel G, Bird CP, Bray-Allen S, Brown JY, Brown AJ, Buckley D, Burton J, Bye J, Carder C, Chapman JC, Clark SY, Clarke G, Clee C, Cobley V, Collier RE, Corby N, Coville GJ, Davies J, Deadman R, Dunn M, Earthrowl M, Ellington AG, Errington H, Frankish A, Frankland J, French L, Garner P, Garnett J, Gay L, Ghori MR, Gibson R, Gilby LM, Gillett W, Glithero RJ, Grafham DV, Griffiths C, Griffiths-Jones S, Grocock R, Hammond S, Harrison ES, Hart E, Haugen E, Heath PD, Holmes S, Holt K, Howden PJ, Hunt AR, Hunt SE, Hunter G, Isherwood J, James R, Johnson C, Johnson D, Joy A, Kay M, Kershaw JK, Kibukawa M, Kimberley AM, King A, Knights AJ, Lad H, Laird G, Lawlor S, Leongamornlert DA, Lloyd DM, Loveland J, Lovell J, Lush MJ, Lyne R, Martin S, Mashreghi-Mohammadi M, Matthews L, Matthews NS, McLaren S, Milne S, Mistry S, Moore MJ, Nickerson T, O'Dell CN, Oliver K, Palmeiri A, Palmer SA, Parker A, Patel D, Pearce AV, Peck AI, Pelan S, Phelps K, Phillimore BJ, Plumb R, Rajan J, Raymond C, Rouse G, Saenphimmachak C, Sehra HK, Sheridan E, Shownkeen R, Sims S, Skuce CD, Smith M, Steward C, Subramanian S, Sycamore N, Tracey A, Tromans A, Van Helmond Z, Wall M, Wallis JM, White S, Whitehead SL, Wilkinson JE, Willey DL, Williams H, Wilming L, Wray PW, Wu Z, Coulson A, Vaudin M, Sulston JE, Durbin R, Hubbard T, Wooster R, Dunham I, Carter NP, McVean G, Ross MT, Harrow J, Olson MV, Beck S, Rogers J, Bentley DR, Banerjee R, Bryant SP, Burford DC, Burrill WD, Clegg SM, Dhami P, Dovey O, Faulkner LM, Gribble SM, Langford CF, Pandian RD, Porter KM, Prigmore E: The DNA sequence and biological annotation of human chromosome 1. Nature. 2006 May 18;441(7091):315-21. [Article]
  5. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
  6. Fujita F, Taniguchi Y, Kato T, Narita Y, Furuya A, Ogawa T, Sakurai H, Joh T, Itoh M, Delhase M, Karin M, Nakanishi M: Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling. Mol Cell Biol. 2003 Nov;23(21):7780-93. [Article]
  7. Han KJ, Su X, Xu LG, Bin LH, Zhang J, Shu HB: Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways. J Biol Chem. 2004 Apr 9;279(15):15652-61. Epub 2004 Jan 22. [Article]
  8. Huang J, Liu T, Xu LG, Chen D, Zhai Z, Shu HB: SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways. EMBO J. 2005 Dec 7;24(23):4018-28. Epub 2005 Nov 10. [Article]
  9. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J: Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005 Oct 20;437(7062):1167-72. Epub 2005 Sep 21. [Article]
  10. Ryzhakov G, Randow F: SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK. EMBO J. 2007 Jul 11;26(13):3180-90. Epub 2007 Jun 14. [Article]
  11. Diao F, Li S, Tian Y, Zhang M, Xu LG, Zhang Y, Wang RP, Chen D, Zhai Z, Zhong B, Tien P, Shu HB: Negative regulation of MDA5- but not RIG-I-mediated innate antiviral signaling by the dihydroxyacetone kinase. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11706-11. Epub 2007 Jun 28. [Article]
  12. Soulat D, Burckstummer T, Westermayer S, Goncalves A, Bauch A, Stefanovic A, Hantschel O, Bennett KL, Decker T, Superti-Furga G: The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. EMBO J. 2008 Aug 6;27(15):2135-46. doi: 10.1038/emboj.2008.126. Epub 2008 Jun 26. [Article]
  13. Schroder M, Baran M, Bowie AG: Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation. EMBO J. 2008 Aug 6;27(15):2147-57. doi: 10.1038/emboj.2008.143. Epub 2008 Jul 17. [Article]
  14. Friedman CS, O'Donnell MA, Legarda-Addison D, Ng A, Cardenas WB, Yount JS, Moran TM, Basler CF, Komuro A, Horvath CM, Xavier R, Ting AT: The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep. 2008 Sep;9(9):930-6. doi: 10.1038/embor.2008.136. Epub 2008 Jul 18. [Article]
  15. Prins KC, Cardenas WB, Basler CF: Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKepsilon and TBK-1. J Virol. 2009 Apr;83(7):3069-77. doi: 10.1128/JVI.01875-08. Epub 2009 Jan 19. [Article]
  16. Oppermann FS, Gnad F, Olsen JV, Hornberger R, Greff Z, Keri G, Mann M, Daub H: Large-scale proteomics analysis of the human kinome. Mol Cell Proteomics. 2009 Jul;8(7):1751-64. doi: 10.1074/mcp.M800588-MCP200. Epub 2009 Apr 15. [Article]
  17. Renner F, Moreno R, Schmitz ML: SUMOylation-dependent localization of IKKepsilon in PML nuclear bodies is essential for protection against DNA-damage-triggered cell death. Mol Cell. 2010 Feb 26;37(4):503-15. doi: 10.1016/j.molcel.2010.01.018. [Article]
  18. Wang H, Ryu WS: Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion. PLoS Pathog. 2010 Jul 15;6(7):e1000986. doi: 10.1371/journal.ppat.1000986. [Article]
  19. Clark K, Peggie M, Plater L, Sorcek RJ, Young ER, Madwed JB, Hough J, McIver EG, Cohen P: Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104. doi: 10.1042/BJ20101701. [Article]
  20. Xie X, Zhang D, Zhao B, Lu MK, You M, Condorelli G, Wang CY, Guan KL: IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6474-9. doi: 10.1073/pnas.1016132108. Epub 2011 Apr 4. [Article]
  21. Pythoud C, Rodrigo WW, Pasqual G, Rothenberger S, Martinez-Sobrido L, de la Torre JC, Kunz S: Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKepsilon. J Virol. 2012 Aug;86(15):7728-38. doi: 10.1128/JVI.00187-12. Epub 2012 Apr 24. [Article]
  22. Zhou AY, Shen RR, Kim E, Lock YJ, Xu M, Chen ZJ, Hahn WC: IKKepsilon-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex. Cell Rep. 2013 Mar 28;3(3):724-33. doi: 10.1016/j.celrep.2013.01.031. Epub 2013 Feb 28. [Article]
  23. Gu L, Fullam A, Brennan R, Schroder M: Human DEAD box helicase 3 couples IkappaB kinase epsilon to interferon regulatory factor 3 activation. Mol Cell Biol. 2013 May;33(10):2004-15. doi: 10.1128/MCB.01603-12. Epub 2013 Mar 11. [Article]
  24. Rajsbaum R, Versteeg GA, Schmid S, Maestre AM, Belicha-Villanueva A, Martinez-Romero C, Patel JR, Morrison J, Pisanelli G, Miorin L, Laurent-Rolle M, Moulton HM, Stein DA, Fernandez-Sesma A, tenOever BR, Garcia-Sastre A: Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKepsilon kinase-mediated antiviral response. Immunity. 2014 Jun 19;40(6):880-95. doi: 10.1016/j.immuni.2014.04.018. Epub 2014 May 29. [Article]
  25. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR: Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB12010Fostamatinibapproved, investigationalunknowninhibitorDetails