Viral nucleic acids are sensed by cellular pattern-recognition receptors (PRRs), such as RIG-I-like receptors (RLR). RLRs activate the adaptor protein called mitochondrial antiviral-signaling protein (MAVS). MAVS recruits TBK1 (tumor necrosis factor (TNF) receptor-associated factor (TRAF) family member-associated NF-κB activator (TANK)-binding kinase 1) and/or its close homolog inhibitor-kappa-B kinase (IKK) epsilon (IKKε or IKBKE) via TRAFs (Fitzgerald KA et al. 2003; Fang R et al. 2017). The enzymatic activity of TBK1/IKBKE is initiated by phosphorylation at Ser172 located in the T loop of the TBK1 and IKKε kinase domains, which is essential for the enhancement of kinase activity (Shimada T et al. 1999; Kishore N et al. 2002; Ma X et al. 2012; Gu L et al. 2013). TBK1 forms a homodimer (Larabi A et al. 2013; Tu D et al. 2013) and structural studies suggest that dimerization of TBK1 precludes autophosphorylation and activation in cis (Larabi A et al. 2013). IKBKE is also a dimer (Nakatsu Y et al. 2014). Other kinases such as IKKs were also implicated in TBK1/IKBKE activation (Fang R et al. 2017). Further, K63-linked polyubiquitination on Lys30 and Lys401 enhanced TBK1/IKBKE activation in HEK293 cells (Tu D et al. 2013; Zhou AY et al. 2013).
Activated TBK1 and IKBKE in turn 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).
Many viruses have evolved numerous mechanisms to evade antiviral action of type I IFNs by acting at the level of the TBK1/IKBKE kinases. For example, nonstructural protein 13 (nsp13) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) binds and blocks TBK1 phosphorylation, while nsp6 binds TBK1 to suppress TBK1-mediated phosphorylation of IRF3 (Xia H et al. 2020). SARS-CoV-2 membrane protein M interacts with MAVS and TBK1 thus preventing the formation of MAVS signalosome (Zheng Y et al. 2020).