IKKε (IKBKE) is phosphorylated within the activated TLR4 complex

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). <p>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). <p>In this Reactome reaction, IKKε (IKBKE) is trans-autophosphorylated at S172 within the activated TLR4 complex. <br>

κB激酶ε的抑制剂（IKKε，IKBKE）及其近缘同源物TANK结合激酶I（TBK1）在感染后下游于模式识别受体激活过程中被激活（Fitzgerald KA 等人，2003；Hemmi H 等人，2004；Hacker H 与 Karin M，2006；Taft J 等人，2021；Wegner J 等人，2023）。IKKε（IKBKE）的活性，类似于TBK1，受N端激酶结构域（KD）激活环内丝氨酸残基172（S172）磷酸化的调控（Clark 等人，2009）。IKKε的激活，如同TBK1，可能通过自磷酸化或通过特定的蛋白激酶的活性来实现（Clark 等人，2009）。<p>TBK1的结构研究表明，其以二聚体形式组装，这种组装通过TBK1的N端KD、泛素样结构域（ULD）和α-螺旋支架二聚化结构域（SDD）之间的多个界面介导，从而支持了跨自磷酸化模型（Larabi A 等人，2013；Tu D 等人，2013）。在人类胚胎肾293（HEK293）细胞中共表达标记的单体时，IKKε形成同源二聚体（Nakatsu Y 等人，2014）。TBK1和IKKε的ULD参与调控激酶激活、底物展示和下游信号传导（Ikeda F 等人，2007；Tu D 等人，2013）。在激活过程中，IKKε（IKBKE）在赖氨酸30和401处被K63连接的多泛素化修饰（Zhou AY 等人，2013）。IKKε和TBK1的泛素化位点及二聚化接触位点均得到保守（Tu D 等人，2013；Zhou AY 等人，2013）。这些发现表明，IKKε和TBK1均通过涉及二聚化、磷酸化和泛素化的相似激活机制进行调控。激活的IKKε（IKBKE）和TBK1磷酸化干扰素（IFN）调节因子3（IRF3）和IRF7，导致IFN的产生（Fitzgerald KA 等人，2003；Hemmi H 等人，2004；Hacker H 与 Karin M，2006；Taft J 等人，2021；Wegner J 等人，2023）。<p>在本Reactome反应中，IKKε（IKBKE）在激活的TLR4复合物中于S172位点发生跨自磷酸化。