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== Function ==
== 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, which leads to a negative impact on insulin sensitivity. Phosphorylates AKT1.<ref>{{cite journal|url=http://www.uniprot.org/uniprot/Q14164 |title=Inhibitor of nuclear factor kappa-B kinase subunit epsilon}}</ref>
[[Serine/threonine kinase]] that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the [[Interferon type I|type I IFN]], [[NFKB|NF-kappa-B]] and [[STAT protein|STAT]] signaling. Also involved in [[TNFA]] and inflammatory [[cytokine]]s, like [[Interleukin-1]], signaling. Following activation of [[Pattern recognition receptor|viral RNA sensors]], such as [[RIG-I-like receptor]]s, associates with [[DDX3X]] and [[Phosphorylation|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 [[IFNB1|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 [[IPS-1|IPS1/MAVS]], [[TANK (gene)|TANK]], [[AZI2|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 (gene)|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 [[Interferon-stimulated gene|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 [[IRF9|ISGF3]] (STAT1:[[STAT2]]:IRF9) complexes compared to GAF (gamma-activation factor) (STAT1:STAT1) complexes, in this way regulating the balance between [[Interferon type I|type I]] and [[Interferon type II|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]].<ref>{{cite journal|url=https://www.uniprot.org/uniprot/Q14164 |title=Inhibitor of nuclear factor kappa-B kinase subunit epsilon}}</ref>


== Clinical significance ==
== Clinical significance ==
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*{{cite journal  |vauthors=tenOever BR, Sharma S, Zou W, etal |title=Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity. |journal=J. Virol. |volume=78 |issue= 19 |pages= 10636–49 |year= 2004 |pmid= 15367631 |doi= 10.1128/JVI.78.19.10636-10649.2004  | pmc=516426 }}
*{{cite journal  |vauthors=tenOever BR, Sharma S, Zou W, etal |title=Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity. |journal=J. Virol. |volume=78 |issue= 19 |pages= 10636–49 |year= 2004 |pmid= 15367631 |doi= 10.1128/JVI.78.19.10636-10649.2004  | pmc=516426 }}
*{{cite journal  |vauthors=Buss H, Dörrie A, Schmitz ML, etal |title=Constitutive and interleukin-1-inducible phosphorylation of p65 NF-<nowiki/>{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-<nowiki/>{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription. |journal=J. Biol. Chem. |volume=279 |issue= 53 |pages= 55633–43 |year= 2005 |pmid= 15489227 |doi= 10.1074/jbc.M409825200 }}
*{{cite journal  |vauthors=Buss H, Dörrie A, Schmitz ML, etal |title=Constitutive and interleukin-1-inducible phosphorylation of p65 NF-<nowiki/>{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-<nowiki/>{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription. |journal=J. Biol. Chem. |volume=279 |issue= 53 |pages= 55633–43 |year= 2005 |pmid= 15489227 |doi= 10.1074/jbc.M409825200 }}
*{{cite journal|url=http://www.uniprot.org/uniprot/Q14164 |title=Inhibitor of nuclear factor kappa-B kinase subunit epsilon}}
*{{cite journal|url=https://www.uniprot.org/uniprot/Q14164 |title=Inhibitor of nuclear factor kappa-B kinase subunit epsilon}}
{{refend}}
{{refend}}


Latest revision as of 07:34, 30 June 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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 IKBKE gene.[1][2][3]

Interactions

IKBKE has been shown to interact with TANK.[4]

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 (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.[5]

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.[6]

References

  1. ↑ 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. PMID 10421793.
  2. ↑ Peters RT, Liao SM, Maniatis T (July 2000). "IKKepsilon is part of a novel PMA-inducible IkappaB kinase complex". Mol Cell. 5 (3): 513–22. doi:10.1016/S1097-2765(00)80445-1. PMID 10882136.
  3. ↑ "Entrez Gene: IKBKE inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon".
  4. ↑ Nomura F, Kawai T, Nakanishi K, Akira S (March 2000). "NF-kappaB activation through IKK-i-dependent I-TRAF/TANK phosphorylation". Genes Cells. 5 (3): 191–202. doi:10.1046/j.1365-2443.2000.00315.x. PMID 10759890.
  5. ↑ "Inhibitor of nuclear factor kappa-B kinase subunit epsilon".
  6. ↑ Llona-Minguez S, Baiget J, Mackay SP (2013). "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharm. Pat. Anal. 2 (4): 481–498. doi:10.4155/ppa.13.31. PMID 24237125.

Further reading


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