Pathogen-induced inflammatory signaling pathways lead to the activation of inhibitor of kappaB kinase epsilon (IKKε, IKBKE) and its close homolog TANK-binding kinase 1 (TBK1). Both TBK1 and IKKε (IKBKE) are serine/threonine kinases, which 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; Taft J et al., 2021; Wegner J et al., 2023).
This Reactome event shows recruitment of IKKε (IKBKE) to the activated TLR4 complex, followed by homodimerization of IKKε (Zhou AY et al., 2013; Nakatsu Y et al., 2014).
Both TBK1 and IKKε (IKBKE) are regulated through similar activation mechanisms involving phosphorylation and ubiquitination (Ikeda F et al., 2007; Tu D et al., 2013; Zhou AY et al., 2013). Structural studies of TBK1 reveal a dimeric assembly that is mediated by several interfaces involving an N-terminal kinase domain (KD), 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). Although there is no structural data on dimerization of IKKε (IKBKE), the dimer contacts are conserved in IKBKE and TBK1 (Tu D et al., 2013). The C-terminal region of IKKε contributes to the dimer formation (Nakatsu Y et al., 2014).
Activated IKKε (IKBKE) and TBK1 phosphorylate interferon (IFN) regulatory factor 3 (IRF3) and IRF7 leading to type I interferon (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). IKKε and TBK1 exhibit functional redundancy with the ability to compensate for each other's functions (Fitzgerald KA et al., 2003; Taft J et al., 2021; Wegner J et al., 2023). For instance, TBK1 has been shown to downregulate the protein expression of IKKε (IKBKE) in human myeloid cells and increased IKKε expression compensated for the loss of TBK1 ensuring efficient type I IFN responses in conditions of TBK1 deficiency (Wegner J et al., 2023). These findings are supported by functional studies using genetic mouse model (Eren RO et al., 2024).
