IKKε (IKBKE) is phosphorylated within the activated TLR3 complex

Stable Identifier
R-HSA-9830706
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Influenza A virus, Rotavirus, Hepatitis B virus, Hepatitis C Virus, Human herpesvirus 1
Compartment
endosome membrane, cytosol
Synonyms
IKBKE is phosphorylated within IKBKE:K63polyUb-TANK:K63pUb-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14
ReviewStatus
5/5
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IKKε (IKBKE) is phosphorylated within the activated TLR3 complex
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Inhibitor of kappaB kinase epsilon (IKKε, IKBKE) and its close homolog TANK-binding kinase I (TBK1) are activated downstream of pattern-recognition receptor activation upon infection (Fitzgerald KA et al., 2003; Hemmi H et al., 2004; Hacker H & Karin M 2006; Taft J et al., 2021; Wegner J et al., 2023). Activity of IKKε (IKBKE), like that of TBK1, is regulated by the phosphorylation of a serine residue 172 (S172) within the activation loop of the N-terminal kinase domain (KD) (Clark et al., 2009). The activation of IKKε, like TBK1, may occur through autophosphorylation or via activity of a distinct protein kinase (Clark et al., 2009).

Structural studies of TBK1 reveal a dimeric assembly which is mediated by several interfaces involving the N-terminal KD, a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD) of TBK1, thus supporting a model of trans-autophosphorylation (Larabi A et al., 2013; Tu D et al., 2013). IKKε forms homodimers upon co-expression of tagged monomers in human embryonic kidney 293 (HEK293) cells (Nakatsu Y et al., 2014). The ULDs of TBK1 and IKKε are involved in the control of kinase activation, substrate presentation, and downstream signaling (Ikeda F et al., 2007; Tu D et al., 2013). Upon activation, IKKε (IKBKE) is modified by K63-linked polyubiquitination on lysines 30 and 401 (Zhou AY et al. 2013). The ubiquitination sites and dimer contacts are conserved in IKKε and TBK1 (Tu D et al., 2013; Zhou AY et al., 2013). These findings suggest that both IKKε and TBK1 are regulated through similar activation mechanisms involving dimerization, phosphorylation, and ubiquitination. Activated IKKε (IKBKE) and TBK1 phosphorylate interferon (IFN) regulatory factor 3 (IRF3) and IRF7 leading to IFN production (Fitzgerald KA et al., 2003; Hemmi H et al., 2004; Hacker H & Karin M 2006; Taft J et al., 2021; Wegner J et al., 2023).

In this Reactome reaction, IKKε (IKBKE) is trans-autophosphorylated at S172 within the activated TLR3 complex.

Literature References
PubMed ID Title Journal Year
15210742 The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection

Takeuchi, O, Hoshino, K, Sanjo, H, Takeda, K, Sato, S, Yamamoto, M, Kaisho, T, Kawai, T, Hemmi, H

J Exp Med 2004
17047224 Regulation and function of IKK and IKK-related kinases

Karin, M, Hacker, H

Sci STKE 2006
12692549 IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway

Maniatis, T, Golenbock, DT, McWhirter, SM, Latz, E, Rowe, DC, Liao, SM, Fitzgerald, KA, Faia, KL, Coyle, AJ

Nat Immunol 2003
23453971 Crystal structure and mechanism of activation of TANK-binding kinase 1

Devos, JM, Nanao, MH, Ng, SL, Round, A, Larabi, A, Panne, D, Maniatis, T

Cell Rep 2013
Participants
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Output
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Authored
Shamovsky, V  (2023-02-10)
Reviewed
Munitić, I  (2024-02-28)
Franjkić, T  (2024-02-28)
Created
Shamovsky, V  (2023-03-13)
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