TBK1 is ubiquitinated within TBK1:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR4

Pathogen‑associated inflammatory signaling pathways result in activation of TANK‑binding kinase 1 (TBK1) and its close homolog inhibitor of kappaB kinase epsilon (IKKε , IKBKE). 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; Taft J et al., 2021; Wegner J et al., 2023). Structural studies of TBK1 reveal a dimeric assembly that is mediated by several interfaces involving an N-terminal kinase domain (KD), an 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 IKBKE) is involved in the control of kinase activation, substrate presentation, and downstream signaling (Ikeda F et al., 2007; Tu D et al., 2013). TBK1 dimer is a subject to K63‑linked polyubiquitination on lysines 30 (K30) and 401 (K401) (Tu D et al., 2013). Activation of TBK1 rearranges the N-terminal KD into an active conformation while maintaining the overall dimer conformation (Larabi A et al., 2013). The E3 Ub ligases that ubiquitinate TBK1 at K30 and K401 in response to various stimuli are reviewed by Runde AP et al. (2022). <p>This Reactome reaction shows the ubiquitination of TBK1 at K30 and K401 within the activated TLR4 complex.

病原体相关炎症信号通路导致TANK结合激酶1（TBK1）及其近缘同源物κB激酶ε（IKKε，IKBKE）的激活。活化的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；Taft J 等人，2021；Wegner J 等人，2023）。对TBK1的结构研究揭示了其以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）和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IKBKE）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）。TBK1二聚体在赖氨酸30（K30）和401（K401）处受到K63连接的多泛素化（Tu D 等人，2013）。TBK1的激活导致其N端KD重排成活性构象，同时保持整体二聚体构象（Larabi A 等人，2013）。响应于各种刺激，在K30和K401处泛素化TBK1的E3泛素连接酶由Runde AP 等人综述（2022年）。此Reactome反应显示了在激活的TLR4复合物内，TBK1在K30和K401处的泛素化。