Inhibitor of nuclear factor kappa-B kinase subunit epsilon also known as I-kappa-B kinase epsilon or IKK-epsilon is an
enzyme that in humans is encoded by the IKBKEgene.[5][6][7]
It is a
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
phosphorylatesinterferon 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 (TANK-binding kinase 1-binding protein 1) 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 (gamma-activation factor) (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, which leads to a negative impact on
insulin sensitivity. Phosphorylates
AKT1.[9]
Clinical significance
Inhibition of
IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and
TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.[10]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Shimada T, Kawai T, Takeda K, Matsumoto M, Inoue J, Tatsumi Y, Kanamaru A, Akira S (September 1999). "IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases". Int Immunol. 11 (8): 1357–62.
doi:
10.1093/intimm/11.8.1357.
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Nagase T, Seki N, Tanaka A, et al. (1996). "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. 2 (4): 167–74, 199–210.
doi:
10.1093/dnares/2.4.167.
PMID8590280.
Aupperle KR, Yamanishi Y, Bennett BL, et al. (2002). "Expression and regulation of inducible IkappaB kinase (IKK-i) in human fibroblast-like synoviocytes". Cell. Immunol. 214 (1): 54–9.
doi:
10.1006/cimm.2002.1885.
PMID11902829.
Fitzgerald KA, McWhirter SM, Faia KL, et al. (2003). "IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway". Nat. Immunol. 4 (5): 491–6.
doi:
10.1038/ni921.
PMID12692549.
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Matsuda A, Suzuki Y, Honda G, et al. (2003). "Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways". Oncogene. 22 (21): 3307–18.
doi:
10.1038/sj.onc.1206406.
PMID12761501.
S2CID38880905.
Bouwmeester T, Bauch A, Ruffner H, et al. (2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. 6 (2): 97–105.
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