TBK1 is phosphorylated within the activated TLR3 complex

TANK-binding kinase I (TBK1) and its close homolog inhibitor of kappaB kinase epsilon (IKKε or IKBKE) are serine/threonine protein kinases, that are activated by pattern-recognition receptors upon infection. Activity of both TBK1 and IKKε (IKBKE) 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 TBK1 and IKKε 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 an 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). 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). Upon activation, TBK1 is modified by K63-linked polyubiquitination on lysines 30 (K30) and K401 (Tu D et al., 2013). Ubiquitination of TBK1 leads to conformational changes that facilitate activation of the N-terminal KD while maintaining the overall dimer conformation (Larabi A et al., 2013). The ubiquitination and phosphorylation sites, as well as dimer contacts, are conserved in the close homolog IKKε (IKBKE) suggesting that both kinases are regulated through similar activation mechanisms (Tu D et al., 2013; Zhou AY et al., 2013). Activated TBK1 then phosphorylates IRF3 and IRF7. <p>TBK1, K63‑polyubiquitinated on K30 and K401, interacts with ubiquitin-binding adaptor protein optineurin (OPTN), which regulates the activity of TBK1 (Pourcelot M et al., 2016). <p>This Reactome event shows TBK1 phosphorylation within the activated TLR3 complex.

TANK 结合激酶 I (TBK1) 及其与 epsilon 激酶激酶 (IKKε 或 IKBKE) 的近缘同源抑制物均为丝氨酸/苏氨酸蛋白激酶，它们在感染过程中由模式识别受体激活。TBK1 和 IKKε (IKBKE) 的活性通过其 N 端激酶结构域 (KD) 激活环内的丝氨酸残基 172 (S172) 的磷酸化进行调节（Clark et al., 2009）。TBK1 和 IKKε 的激活可能通过自磷酸化或通过独特的蛋白激酶的活性实现（Clark et al., 2009）。TBK1 的结构研究表明，其呈现二聚体组装，这一组装通过多个界面介导，涉及 N 端 KD、泛素样结构域 (ULD) 和 TBK1 的 α-螺旋支架二聚化结构域 (SDD)，从而支持了跨自磷酸化的模型（Larabi A et al., 2013; Tu D et al., 2013）。TBK1 的 ULD（及 IKKε）参与调控激酶激活、底物展示和下游信号转导（Ikeda F et al., 2007; Tu D et al., 2013）。激活后，TBK1 在赖氨酸 30 (K30) 和 K401（Tu D et al., 2013）上发生 K63 连接的多泛素化修饰。TBK1 的泛素化导致构象变化，从而有利于 N 端 KD 的激活，同时保持整体的二聚体构象（Larabi A et al., 2013）。泛素化和磷酸化位点，以及二聚体接触位点在近缘同源 IKKε (IKBKE) 中得以保守，这表明两种激酶均通过类似的激活机制进行调节（Tu D et al., 2013; Zhou AY et al., 2013）。激活的 TBK1 随后磷酸化 IRF3 和 IRF7。<p>TBK1，在 K30 和 K401 位点 K63 多泛素化修饰，与泛素结合适配蛋白 optineurin (OPTN) 相互作用，调节 TBK1 的活性（Pourcelot M et al., 2016）。<p>此 Reactome 事件展示了激活的 TLR3 复合物内 TBK1 的磷酸化。