Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) and its close homolog, inhibitor of kappaB kinase epsilon (IKKε, IKBKE), induce type I interferon (IFN) expression 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).
This Reactome event shows recruitment of TBK1 to the activated Toll-like receptor 4 (TLR4) complex.
TBK1 and IKKε (IKBKE) are found to interact with scaffold proteins TANK (TRAF family member associated NF-kappa-B activator), NAP1 (NAK-associated protein 1), and SINTBAD (similar to NAP1 TBK1 adaptor), which connect TBK1 and IKKε to pathogen-activated signaling complexes such as TLR4 (Pomerantz JL and Baltimore D 1999; Guo B and Cheng G 2007; Gatot JC et al., 2007; Ryzhakov G and Randow F 2007; Goncalves A et al., 2011). In addition, studies demonstrate an essential role for the E3 ubiquitin ligase TRAF3 in the activation of TBK1 (Oganesyan G et al., 2006; Hacker H et al 2006). Further, structural studies of TBK1 revealed a dimeric assembly that is mediated by several interfaces involving an N-terminal kinase domain (KD), 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 ULDs of TBK1 and IKKε are 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 and 401 (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 ubiquitination sites and dimer contacts are conserved in the close homolog IKKε (IKBKE) (Tu D et al., 2013). The activation of TBK1 and IKKε may occur through autophosphorylation or via activity of a distinct protein kinase (Clark et al., 2009). TBK1 binding to optineurin (OPTN), an autophagy receptor, regulates TBK1-mediated IRF3 activation and type I interferon responses (reviewed by Markovinovic A et al., 2017; Outlioua A et al., 2018; Slowicka K & van Loo G 2018).
