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Details on Person TBK1 (tumor necrosis factor (TNF) receptor-associated factor...
| Class:Id | Summation:9705146 |
|---|---|
| _displayName | TBK1 (tumor necrosis factor (TNF) receptor-associated factor... |
| _timestamp | 2021-02-17 07:03:20 |
| created | [InstanceEdit:9705144] Shamovsky, Veronica, 2020-10-21 |
| literatureReference | [LiteratureReference:2408458] Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation [LiteratureReference:5362581] Crystal structure and mechanism of activation of TANK-binding kinase 1 [LiteratureReference:9705140] Effects of ALS-associated TANK binding kinase 1 mutations on protein-protein interactions and kinase activity [LiteratureReference:5362611] Structure and ubiquitination-dependent activation of TANK-binding kinase 1 [LiteratureReference:9705131] Functionally distinct effects of the C-terminal regions of IKKε and TBK1 on type I IFN production |
| modified | [InstanceEdit:9705694] Shamovsky, Veronica, 2020-10-28 [InstanceEdit:9713626] Shamovsky, Veronica, 2021-01-27 [InstanceEdit:9715437] Shamovsky, Veronica, 2021-02-17 |
| text | 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. |
| (summation) | [Reaction:9705145] TBK1, IKBKE form homodimers [Homo sapiens] |
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No pathways have been reviewed or authored by TBK1 (tumor necrosis factor (TNF) receptor-associated factor... (9705146)
