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Q9R0T8 (IKKE_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 118. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Inhibitor of nuclear factor kappa-B kinase subunit epsilon

Short name=I-kappa-B kinase epsilon
Short name=IKK-E
Short name=IKK-epsilon
Short name=IkBKE
EC=2.7.11.10
Alternative name(s):
Inducible I kappa-B kinase
Short name=IKK-i
Gene names
Name:Ikbke
Synonyms:Ikke, Ikki
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length717 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Ref.5 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11

Catalytic activity

ATP + [I-kappa-B protein] = ADP + [I-kappa-B phosphoprotein].

Enzyme regulation

Kinase activity is inhibited competitively by amlexanox. Ref.11

Subunit structure

Homodimer. 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, IKBKB, IKBKG and MYD88. Interacts with DDX3X; the interaction is found to be induced upon virus infection. Ref.6

Subcellular location

Cytoplasm By similarity. Nucleus By similarity. NucleusPML body By similarity. Note: Targeting to PML nuclear bodies upon DNA damage is TOPORS-dependent By similarity.

Tissue specificity

Expressed in bone marrow-derived macrophages and at low levels in liver and white adipose tissue (at protein level). Detected in muscle and lung. Ref.7 Ref.8 Ref.11

Induction

Induced by lipopolysaccharide (LPS) and TNFA. Under high-fat diet, highly induced (via NF-kappa-B) in adipocytes and M1-polarized adipose tissue macrophages. Ref.8 Ref.10 Ref.11

Post-translational modification

Sumoylation by TOPORS upon DNA damage is required for protection of cells against DNA damage-induced cell death. Desumoylated by SENP1 By similarity.

Autophosphorylated and phosphorylated by IKBKB/IKKB. Phosphorylation at Ser-172 is enhanced by the interaction with DDX3X. Phosphorylated at Thr-503 upon IFN activation. Ref.7

'Lys-63'-linked polyubiquitinated at Lys-30 and Lys-403 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 By similarity.

Disruption phenotype

Animals are hypersusceptible to influenza virus infection because of a defect in the activation of a subset of type 1 IFN-stimulated genes, however the amounts of IFNB produced are normals. Lungs of mice infected 7 days with influenza virus exhibit an inflammatory infiltrate consisting of lymphocytes, macrophages and neutrophils. After West Nile virus infection, animals display earlier neurological symptoms, a higher degree of neurovirulence and a failure to recover, compared to wild type. Animals are protected from high-fat diet-induced obesity, liver and adipose inflammation, hepatic steatosis and insulin resistance. They show an increased energy expenditure and thermogenesis and maintain insulin sensitivity in liver and adipose tissue. Ref.5 Ref.7 Ref.8 Ref.9 Ref.11

Sequence similarities

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.

Contains 1 protein kinase domain.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Traf3ip2Q8N7N63EBI-6664658,EBI-646165

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 717717Inhibitor of nuclear factor kappa-B kinase subunit epsilon
PRO_0000086018

Regions

Domain9 – 315307Protein kinase
Nucleotide binding15 – 239ATP By similarity
Region385 – 650266Interaction with DDX3X By similarity
Region452 – 47322Leucine-zipper

Sites

Active site1351Proton acceptor By similarity
Binding site381ATP By similarity

Amino acid modifications

Modified residue1721Phosphoserine; by autocatalysis and IKKB
Modified residue5031Phosphothreonine Ref.7
Modified residue6651Phosphoserine By similarity
Cross-link30Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link231Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) By similarity
Cross-link403Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Experimental info

Mutagenesis381K → A: Dominant negative. Ref.7
Sequence conflict4711S → G in BAA85154. Ref.1
Sequence conflict4831A → S in BAA85154. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q9R0T8 [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: 0863ECC180AE385A

FASTA71780,953
        10         20         30         40         50         60 
MQSTTNYLWH TDDLLGQGAT ASVYKARNKK SGEVVAVKVF NSASYRRPPE VQVREFEVLR 

        70         80         90        100        110        120 
RLNHQNIVKL FAVEETGGSR QKVLIMEYCS SGSLLSVLED PENTFGLSEE EFLVVLRCVV 

       130        140        150        160        170        180 
AGMNHLRENG IVHRDIKPGN IMRLVGEEGQ SIYKLSDFGA ARKLDDDEKF VSVYGTEEYL 

       190        200        210        220        230        240 
HPDMYERAVL RKPQQKAFGV TVDLWSIGVT LYHAATGSLP FIPFGGPRRN KEIMYRITTE 

       250        260        270        280        290        300 
KPAGAISGTQ KQENGPLEWS YSLPITCRLS MGLQNQLVPI LANILEVEED KCWGFDQFFA 

       310        320        330        340        350        360 
ETSDILQRTV IHVFSLPQAV LHHVYIHAHN TIAIFLEAVY EQTNVTPKHQ EYLFEGHPCV 

       370        380        390        400        410        420 
LEPSLSAQHI AHTAASSPLT LFSMSSDTPK GLAFRDPALD VPKFVPKVDL QADYSTAKGV 

       430        440        450        460        470        480 
LGAGYQALWL ARVLLDGQAL MLRGLHWVLE VLQDTCQQTL EVTRTALLYL SSSLGTERFS 

       490        500        510        520        530        540 
SGAGMPDVQE RKEATELRTR LQTLSEILSK CSHNVTETQR SLSCLGEELL KNRDQIHEDN 

       550        560        570        580        590        600 
KSIQKIQCCL DKMHFIYKQF KKSRMRPGLS YNEEQIHKLD KVNFSHLAKR LLQVFQEECV 

       610        620        630        640        650        660 
QTYQVSLVTH GKRMRQVQRA QNHLHLIGHS VATCNSEARG AQESLNKIFD QLLLDRASEQ 

       670        680        690        700        710 
GAEVSPQPMA PHPGPDPKDL VFHMQELCND MKLLAFDLQD NNRLIERLHR VPSAPDV 

« Hide

References

« Hide 'large scale' references
[1]"IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases."
Shimada T., Kawai T., Takeda K., Matsumoto M., Inoue J., Tatsumi Y., Kanamaru A., Akira S.
Int. Immunol. 11:1357-1362(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Macrophage.
[2]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6J and NOD.
Tissue: Bone marrow and Thymus.
[3]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6J.
[4]Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection."
Hemmi H., Takeuchi O., Sato S., Yamamoto M., Kaisho T., Sanjo H., Kawai T., Hoshino K., Takeda K., Akira S.
J. Exp. Med. 199:1641-1650(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[6]"SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK."
Ryzhakov G., Randow F.
EMBO J. 26:3180-3190(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AZI2; TANK AND TBKBP1.
[7]"Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity."
Tenoever B.R., Ng S.L., Chua M.A., McWhirter S.M., Garcia-Sastre A., Maniatis T.
Science 315:1274-1278(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN STAT1 ACTIVATION, PHOSPHORYLATION AT THR-503, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, MUTAGENESIS OF LYS-38.
[8]"The protein kinase IKKepsilon regulates energy balance in obese mice."
Chiang S.H., Bazuine M., Lumeng C.N., Geletka L.M., Mowers J., White N.M., Ma J.T., Zhou J., Qi N., Westcott D., Delproposto J.B., Blackwell T.S., Yull F.E., Saltiel A.R.
Cell 138:961-975(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ENERGY BALANCE, DISRUPTION PHENOTYPE, INDUCTION BY HIGH-FAT DIET, TISSUE SPECIFICITY.
[9]"Inhibitor of kappaB kinase epsilon (IKK(epsilon)), STAT1, and IFIT2 proteins define novel innate immune effector pathway against West Nile virus infection."
Perwitasari O., Cho H., Diamond M.S., Gale M. Jr.
J. Biol. Chem. 286:44412-44423(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN STAT1 ACTIVATION, DISRUPTION PHENOTYPE.
[10]"IkappaB kinase epsilon (IKK(epsilon)) regulates the balance between type I and type II interferon responses."
Ng S.L., Friedman B.A., Schmid S., Gertz J., Myers R.M., Tenoever B.R., Maniatis T.
Proc. Natl. Acad. Sci. U.S.A. 108:21170-21175(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION REGULATION IN IFN RESPONSE.
[11]"An inhibitor of the protein kinases TBK1 and IKK-[?] improves obesity-related metabolic dysfunctions in mice."
Reilly S.M., Chiang S.H., Decker S.J., Chang L., Uhm M., Larsen M.J., Rubin J.R., Mowers J., White N.M., Hochberg I., Downes M., Yu R.T., Liddle C., Evans R.M., Oh D., Li P., Olefsky J.M., Saltiel A.R.
Nat. Med. 19:313-321(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ENERGY BALANCE, DISRUPTION PHENOTYPE, INDUCTION BY HIGH-FAT DIET, TISSUE SPECIFICITY, ENZYME REGULATION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB016589 mRNA. Translation: BAA85154.1.
AK088580 mRNA. Translation: BAC40434.1.
AK149911 mRNA. Translation: BAE29161.1.
CT010206 mRNA. Translation: CAJ18414.1.
CH466520 Genomic DNA. Translation: EDL39710.1.
CCDSCCDS15269.1.
RefSeqNP_062751.2. NM_019777.3.
XP_006529824.1. XM_006529761.1.
UniGeneMm.386783.

3D structure databases

ProteinModelPortalQ9R0T8.
SMRQ9R0T8. Positions 2-648.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid208014. 1 interaction.
IntActQ9R0T8. 2 interactions.
STRING10090.ENSMUSP00000054126.

PTM databases

PhosphoSiteQ9R0T8.

Proteomic databases

PRIDEQ9R0T8.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000062108; ENSMUSP00000054126; ENSMUSG00000042349.
GeneID56489.
KEGGmmu:56489.
UCSCuc007cnf.1. mouse.

Organism-specific databases

CTD9641.
MGIMGI:1929612. Ikbke.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00530000063051.
HOGENOMHOG000220867.
HOVERGENHBG008494.
InParanoidQ8C2I3.
KOK07211.
OMAHIYIHAH.
OrthoDBEOG7Z95KH.
TreeFamTF324269.

Enzyme and pathway databases

BRENDA2.7.11.10. 3474.

Gene expression databases

ArrayExpressQ9R0T8.
BgeeQ9R0T8.
CleanExMM_IKBKE.
GenevestigatorQ9R0T8.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio312766.
PROQ9R0T8.
SOURCESearch...

Entry information

Entry nameIKKE_MOUSE
AccessionPrimary (citable) accession number: Q9R0T8
Secondary accession number(s): Q8C2I3
Entry history
Integrated into UniProtKB/Swiss-Prot: June 20, 2001
Last sequence update: July 27, 2011
Last modified: July 9, 2014
This is version 118 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot