RIG?I?like receptors (RLRs) recognize RNAs from various RNA ...

created [InstanceEdit:9705126] Shamovsky, Veronica, 2020-10-21
dbId 9705127
displayName RIG?I?like receptors (RLRs) recognize RNAs from various RNA ...
literatureReference
modified [InstanceEdit:9927237] Shamovsky, Veronica, 2024-11-05
schemaClass Summation
text RIG?I?like receptors (RLRs) recognize RNAs from various RNA viruses and activate the mitochondrial antiviral?signaling protein (MAVS, IPS-1) adaptor protein. MAVS recruits the serine/threonine protein kinase TBK1 (tumor necrosis factor (TNF) receptor?associated factor (TRAF) family member?associated NF??B activator (TANK)?binding kinase 1) and/or its close homolog inhibitor?kappa?B kinase (IKK) epsilon (IKK? or IKBKE) via TRAFs. Imunoprecipitation combined with mass spectrometry (MS)-based proteomic assays identified interactors of endogenous TBK1, such as TANK and NAP1, in SeV or HHV-1 (HSV-1)-infected human acute monocytic leukemia cells (THP?1) cells (Shang L et al. 2018). TBK1 and IKBKE trigger phosphorylation of interferon regulatory factor 3 (IRF3) and IRF7 and subsequent expression of type I interferons (IFNs; IFN??/?). Both TBK1 and IKBKE directly phosphorylate IRF3 and IRF7 targeting identical residues within the C-terminal signal-responsive domain (McWhirter SM et al. 2004; tenOever BR et al. 2004). Type I IFNs can induce the expression of numerous antiviral genes called interferon?stimulated genes (ISGs). Structural studies revealed a dimeric assembly of TBK1 that is stabilized by an extensive network of interactions among the kinase, ubiquitin?like (ULD) and scaffold/dimerization (SDD) domains of TBK1 (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 IKK? (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 homodimer 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?? 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 activation via transautophosphorylation at Ser172 of dimeric TBK1 (Larabi A et al. 2013; Tu D et al. 2013; Ma X et al. 2012). However, familial 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). These observations suggest that TBK1 dimerization is not required for kinase activation. Rather, dimerization seems to increase protein stability and enables efficient kinase?substrate interactions (Ye J et al. 2019).
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