STING:TBK1:IRF3 STING:STING STING recruits TBK1 and IRF3 Authored: Shamovsky, V, 2012-07-09 Pubmed12133833 Pubmed15210742 Pubmed16281057 Pubmed16306936 Pubmed18818105 Pubmed19433799 Pubmed19776740 Pubmed19926846 Pubmed22394562 Pubmed22579474 Reactome Database ID Release 431834939 Reactome, http://www.reactome.org ReactomeREACT_147703 Reviewed: D'Eustachio, P, 2012-07-18 Reviewed: Jin, Lei, 2012-08-18 TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) are central regulators of type-I interferon induction during bacterial or viral infection. TBK1 was found to form complexes with distinct scaffolding proteins that appeared to target TBK1 to different subcellular compartments [Hemmi H et al 2004; Oganesyan G et al 2006; Chariot A et al 2002; Huang J et al 2004]. In dsDNA-stimulated human and mouse cells TBK1 has been shown to move to cytoplasmic punctate structures, where it associates with STING to induce IRF3 activation [Ishikawa H et al 2009; Saitoh T et al 2009; Sun W et al 2009; Tanaka Y and Chen ZJ 2012]. Co-immunoprecipitation assays in HEK 293T cells expressing HA-tagged STING and Flag-tagged TBK1 showed that TBK1 directly interacts with STING. Moreover, glutathione S-transferase (GST) pull-down assays showed that recruitment of TBK1 by STING was enhanced upon c-di-GMP binding [Ouyang S et al 2012].<p>STING was reported to mediate TBK1-dependent activation of transcription factor IRF3 [Zhong B et al 2008; Tanaka Y, and Chen ZJ 2012]. Both TBK1 and IRF3 can directly interact with STING through its C-terminal region [Tanaka Y, and Chen ZJ 2012]. A construct of human STING containing only 39 amino acid residues of its C-terminus (341 to 379) was sufficient to activate IRF3 in cytosolic extracts of HeLa cells. Further mutagenesis studies showed, that two residues, Ser366 and Leu374, within the C-terminal tail of STING were required for IRF3 binding and phosphorylation, but were dispensable for TBK1 binding and activation [Tanaka Y, and Chen ZJ 2012]. Thus, STING is thought to function as a scaffold to recruit cytosolic TBK1 and IRF3, which results in TBK1-dependent phosphorylation of IRF3. has a Stoichiometric coefficient of 2