Reactome | IKKε (IKBKE) is ubiquitinated within the activated TLR4

IKKε (IKBKE) is ubiquitinated within the activated TLR4

Stable Identifier

R-HSA-9823939

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

endosome membrane, cytosol

Synonyms

IKKε (IKBKE) is ubiquitinated within IKBKE:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR4

ReviewStatus

5/5

Locations in the PathwayBrowser

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Immune System (Homo sapiens)

- Innate Immune System (Homo sapiens)
  - Toll-like Receptor Cascades (Homo sapiens)
    - Toll Like Receptor 4 (TLR4) Cascade (Homo sapiens)
      - MyD88-independent TLR4 cascade (Homo sapiens)
        
        TRIF (TICAM1)-mediated TLR4 signaling (Homo sapiens)
        
        Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) (Homo sapiens)
        
        Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 (Homo sapiens)
        
        IKKε (IKBKE) is ubiquitinated within the activated TLR4 (Homo sapiens)

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IKKε (IKBKE) is ubiquitinated within the activated TLR4

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Pathogen-associated inflammatory signaling pathways result in activation of inhibitor of kappaB kinase epsilon (IKKε or IKBKE) and its close homolog TANK-binding kinase 1 (TBK1). Activated TBK1 and IKKε (IKBKE) induce type I interferon production and modulate nuclear factor kappa-B (NF-kappa-B) signaling (Fitzgerald KA et al., 2003; Hemmi H et al., 2004; Gatot JS et al., 2007). Both TBK1 and IKKε are regulated by K63-linked polyubiquitination on lysines 30 (K30) and 401 (K401) (Tu D et al., 2013; Zhou AY et al., 2013). Structural studies of TBK1 reveal a dimeric assembly which is mediated by several interfaces involving kinase domain (KD) at the N-terminus, a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD) of TBK1 (Larabi A et al., 2013; Tu D et al., 2013). The ULD of TBK1 (and IKKε) is involved in the control of kinase activation, substrate presentation, and downstream signaling (Ikeda F et al., 2007; Tu D et al., 2013). Ubiquitination of TBK1 rearranges the N-terminal KD into an active conformation while maintaining the overall dimer conformation (Larabi A et al., 2013). The ubiquitination sites and dimer contacts are conserved in IKKε (IKBKE) suggesting that TBK1 and IKKε are regulated through similar activation mechanisms (Tu D et al., 2013; Zhou AY et al., 2013).

This Reactome event shows ubiquitination of IKKε (IKBKE) at K30 and K401 within the activated TLR4 complex.

Literature References

PubMed ID	Title	Journal	Year
17599067	Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes Dötsch, V, Rozenknop, A, Rogov, V, Nordmeier, RD, Ikeda, F, Akira, S, Dikic, I, Hecker, CM, Hofmann, K	EMBO J	2007
23453969	IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex Shen, RR, Hahn, WC, Chen, ZJ, Xu, M, Lock, YJ, Zhou, AY, Kim, E	Cell Rep	2013