TBK1 (tumor necrosis factor (TNF) receptor-associated factor (TRAF) family member-associated NF-κB activator (TANK)-binding kinase 1) and its close homolog inhibitor-kappa-B kinase (IKK) epsilon (IKKε or IKBKE) are serine/threonine-protein kinases that trigger phosphorylation of interferon regulatory factor 3 (IRF3) and IRF7 and subsequent expression of type I interferons (IFNs; IFN-α/β). Type I IFNs can induce the expression of numerous antiviral genes called interferon-stimulated genes (ISGs). Structural studies revealed a dimeric assembly of TBK1 stabilized by an extensive network of interactions among its kinase, ubiquitin-like (ULD) and scaffold/dimerization (SDD) domains (Larabi A et al. 2013; Tu D et al. 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 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.
Kimura, H, Kubota, T, Matsuoka, M, Otsuki, N, Kato, H, Noda, M, Takeda, M, Nakatsu, Y, Chang, TH, Sakai, K
Helgason, E, Dueber, EC, Ma, X, Bowman, KK, Lee, MW, Phung, QT, Starovasnik, MA, Iyer, RS, Quan, CL
Devos, JM, Nanao, MH, Ng, SL, Round, A, Larabi, A, Panne, D, Maniatis, T
© 2023 Reactome
