IKKε (IKBKE) is ubiquitinated within the activated TLR4

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

病原体相关炎症信号通路导致抑制性κB激酶ε（IKKε或IKBKE）及其近缘同源物TANK结合激酶1（TBK1）的激活。激活的TBK1和IKKε（IKBKE）诱导I型干扰素的产生并调节核因子κB（NF-κB）信号通路（Fitzgerald KA 等人，2003；Hemmi H 等人，2004；Gatot JS 等人，2007）。TBK1和IKKε均受赖氨酸30（K30）和401（K401）上的K63链接多泛素化调控（Tu D 等人，2013；Zhou AY 等人，2013）。TBK1的结构研究揭示了由多个界面介导的二聚体组装，这些界面涉及N端激酶结构域（KD）、泛素样结构域（ULD）以及TBK1的α螺旋支架二聚化结构域（SDD）（Larabi A 等人，2013；Tu D 等人，2013）。TBK1（及IKKε）的ULD参与调控激酶活化、底物展示和下游信号传导（Ikeda F 等人，2007；Tu D 等人，2013）。TBK1的泛素化重组N端KD至活性构象，同时保持整体二聚体构象（Larabi A 等人，2013）。在IKKε（IKBKE）中的泛素化位点及二聚化接触点在IKKε（IKBKE）中得以保留，这表明TBK1和IKKε通过相似的激活机制进行调控（Tu D 等人，2013；Zhou AY 等人，2013）。此Reactome事件展示了在激活的TLR4复合体中，IKKε（IKBKE）在K30和K401位点的泛素化。