Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon

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Homo sapiens
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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.

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).

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.

Literature References
PubMed ID Title Journal Year
15210742 The roles of two IkappaB kinase-related kinases in lipopolysaccharide and

Takeuchi, O, Hoshino, K, Sanjo, H, Takeda, K, Sato, S, Yamamoto, M, Kaisho, T, Kawai, T, Hemmi, H

J Exp Med 2004
15502848 Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling

Sakamoto, S, Elco, CP, Sarkar, SN, Peters, KL, Pal, S, Sen, GC

Nat Struct Mol Biol 2004
17332413 Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity

Garcia-Sastre, A, Chua, MA, Ng, SL, McWhirter, SM, Tenoever, BR, Maniatis, T

Science 2007
14679297 IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts

Fitzgerald, KA, Rowe, DC, McWhirter, SM, Golenbock, DT, Maniatis, T, Rosains, J

Proc Natl Acad Sci U S A 2004
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