TBK1, IKBKE form homodimers

Stable Identifier
R-HSA-9705145
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Influenza A virus, Human respiratory syncytial virus A, Rotavirus, Hepatitis C Virus, Measles virus
Compartment
mitochondrial outer membrane
ReviewStatus
5/5
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TBK1, IKBKE form homodimers
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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.
Literature References
PubMed ID Title Journal Year
24722368 Functionally distinct effects of the C-terminal regions of IKKε and TBK1 on type I IFN production

Kimura, H, Kubota, T, Matsuoka, M, Otsuki, N, Kato, H, Noda, M, Takeda, M, Nakatsu, Y, Chang, TH, Sakai, K

PLoS One 2014
22619329 Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

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

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

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

Cell Rep 2013
Participants
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Output
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Authored
Shamovsky, V  (2020-12-25)
Reviewed
D'Eustachio, P  (2021-01-27)
Ramos, CH  (2021-04-19)
Created
Shamovsky, V  (2020-10-21)
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