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 TLR4 complex.