RIAR-I的受体（RLRS）识别来自各种RNA病毒的RNA，并激活线粒体抗病毒 - 信令蛋白（MAVS）适配器蛋白。Mavs促进丝氨酸/苏氨酸蛋白激酶TBK1（肿瘤坏死因子（TNF）受体相关因子（TRAF）家族构成的NF-κB活化剂（罐） - 耦合激酶1）和/或其关闭同源物抑制剂-Kappa-B激酶（Ikk）epsilon（ikkε或ikbke）通过trafs。与质谱（MS）的蛋白质组学测定结合的Imunoprecipipipitipitipitipition鉴定了内源性TBK1的交互剂，例如罐和NAP1，如罐和NAP1，在SEV或HHV-1（HSV-1） - 摄取的人急性单核细胞白血病细胞（THP-1）细胞（上我。2018年）。TBK1和Ikbke触发干扰素调节因子3（IRF3）和IRF7的磷酸化，随后的I型干扰素（IFNS; IFN-α/β）。TBK1和IKBKE都直接磷酸化IRF3和IRF7靶向C末端信号响应域内的相同残留物（MCWhirter SM等，2004; TENOEVER BR等人2004）。I型IFN可以诱导称为干扰素刺激基因（ISG）的许多抗病毒基因的表达。结构研究揭示了TBK1的二聚体组装，通过TBK1的激酶，泛素样（ULD）和支架/二聚化（SDD）结构域之间的广泛的相互作用网络稳定（Larabi A等，2013; Tu D等人。2013）。 IKBKE was also reported to form dimers (Nakatsu Y et al. 2014). Even though the contacts that stabilize the TBK1 dimer are largely conserved in IKKε (IKBKE), studies reported differences in activation mechanisms between TBK1 and IKBKE (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 homodimer 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 activation via transautophosphorylation at Ser172 of dimeric TBK1 (Larabi A et al. 2013; Tu D et al. 2013; Ma X et al. 2012). However, familial 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). These observations suggest that TBK1 dimerization is not required for kinase activation. Rather, dimerization seems to increase protein stability and enables efficient kinase‑substrate interactions (Ye J et al. 2019).
