TBK1(肿瘤坏死因子(TNF) receptor-associated因子(TRAF)家庭member-associated NF -κB催化剂(坦克)绑定激酶1)及其亲密同族体inhibitor-kappa-B激酶(IKK)ε(IKKε或IKBKE)丝氨酸/ threonine-protein触发的激酶磷酸化的干扰素调节因子3 (IRF3)和IRF7和后续I型干扰素(IFNs;干扰素-α/β)。I型ifn可诱导大量被称为干扰素刺激基因(ISGs)的抗病毒基因的表达。结构研究揭示了TBK1的二聚体组装，由其激酶、泛素样(ULD)和支架/二聚体(SDD)结构域之间广泛的相互作用网络稳定(Larabi a等，2013;Tu D et al. 2013)。也有报道称IKBKE可形成二聚体(Nakatsu Y et al. 2014)。尽管在IKKε (IKBKE)中稳定TBK1二聚体的接触在很大程度上是保守的，但研究报告了TBK1和IKBKE激活机制的差异(Larabi A et al. 2013;Tu D et al. 2013;Nakatsu Y et al. 2014)。 While the C-terminal region was required for dimerization of IKBKE and downstream signaling, a C-terminally truncated fragment of TBK1 formed a dimer both in vitro and in vivo and was able to induce IRF3 phosphorylation (Nakatsu Y et al. 2014). Mutants that interfere with TBK1 dimerization showed significantly reduced trans-autophosphorylation upon expression in human embryonic kidney 293 (HEK293) cells (Larabi A et al. 2013). An intact TBK1 dimer was modified by K63-linked polyubiquitination on lysine 30 and lysine 401, and these modifications were required for TBK1 activation in HEK293 cells (Tu D et al. 2013). Similar findings were reported for IKBKE (Zhou AY et al. 2013). Further, interferon-β expression was ablated in TBK1-/- mouse embryo fibroblasts (MEFs) cells reconstituted with dimerization defective TBK1 mutants (Tu D et al. 2013). Structural studies suggest that TBK1 dimerization is required for kinase activation via transautophosphorylation at Ser172 of dimeric TBK1 (Larabi A et al. 2013; Tu D et al. 2013; Ma X et al. 2012). However, dimerization of TBK1 was not required for TBK1 downstream activity once the activation loop was phosphorylated (Ma X et al. 2012; Larabi A et al. 2013). These observations are supported by findings that amyotrophic lateral sclerosis (ALS)-associated TBK1 mutations in ULD or SDD displayed defects in dimerization of TBK1 without losing kinase activity (Ye J et al. 2019). The Reactome event shows homodimer formation of TBK1 and/or IKBKE in the RIG-I-like receptors (RLRs):mitochondrial antiviral-signaling protein (MAVS) signaling pathway.
