Dimerized phospho-IRF3/IRF7 is transported to the nucleus Dimerization of phosphorylated IRF3/IRF7 TRAF3 binds to TRIF:activated TLR3/4 complex Recruitment of TBK1/IKK epsilon to K63-poly-Ub-TRAF3:TRIF:activated TLR3/TLR4 followed by their phosphorylation Auto-ubiquitination of TRAF3 IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR Phosphorylation of IRF-3/IRF7 and their release from the activated TLR complex PathwayStep6707 PathwayStep6708 PathwayStep6709 PathwayStep6710 PathwayStep6713 PathwayStep6711 PathwayStep6712 Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon Authored: Shamovsky, V, 2010-06-01 Cell stimulation with viral ds RNA leads to the activation of two IKK-related serine/threonine kinases, TBK1 and IKK-i which directly phosphorylate IRF3 and IRF7 promoting their dimerization and translocation into the nucleus. Although both kinases show structural and functional similarities, it seems that TBK1 and IKK-i differ in their regulation of downstream signaling events of TLR3.<p>IRF3 activation and IFN-b production by poly(I:C) are decreased in TBK1-deficient mouse fibroblasts, whereas normal activation was observed in the IKK-i-deficient fibroblasts. However, in double-deficient mouse fibroblasts, the activation of IRF3 is completely abolished, suggesting a partially redundant functions of TBK1 and IKK-i [Hemmi et al 2004].<p>TLR3 recruits and activates PI3 kinase (PI3K), which activates the downstream kinase, Akt, leading to full phosphorylation and activation of IRF-3 [Sarkar SN et al 2004]. When PI3K is not recruited to TLR3 or its activity is blocked, IRF-3 is only partially phosphorylated and fails to bind the promoter of the target gene. Edited: Shamovsky, V, 2010-11-16 GENE ONTOLOGYGO:0035666 Pubmed14679297 Pubmed15210742 Pubmed15502848 Pubmed17332413 Reactome Database ID Release 43936964 Reactome, http://www.reactome.org ReactomeREACT_25148 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30