TBK1, IKBKE are autophosphorylated at Ser172

Stable Identifier
R-HSA-9705320
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Rotavirus, Influenza A virus, Hepatitis C Virus, Measles virus, Severe acute respiratory syndrome coronavirus 2
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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 (IKKε) 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).

Literature References
PubMed ID Title Journal Year
10421793 IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases

Shimada, T, Kawai, T, Takeda, K, Matsumoto, M, Inoue, J, Tatsumi, Y, Kanamaru, A, Akira, S

Int Immunol 1999
22619329 Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

Ma, X, Helgason, E, Phung, QT, Quan, CL, Iyer, RS, Lee, MW, Bowman, KK, Starovasnik, MA, Dueber, EC

Proc. Natl. Acad. Sci. U.S.A. 2012
23453971 Crystal structure and mechanism of activation of TANK-binding kinase 1

Larabi, A, Devos, JM, Ng, SL, Nanao, MH, Round, A, Maniatis, T, Panne, D

Cell Rep 2013
Participants
Participates
Catalyst Activity

protein serine/threonine kinase activity of viral dsRNA:IFIH1, viral dsRNA:K63polyUb-DDX58:MAVS:K63polyUb-TRAF3:2xIKK related kinases TBK1/IKK epsilon [mitochondrial outer membrane]

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