TICAM1-dependent activation of IRF3/IRF7

Stable Identifier
R-HSA-9013973
Type
Pathway
Species
Homo sapiens
Related Species
Rotavirus, Influenza A virus, Hepatitis B virus, Hepatitis C Virus, Human herpesvirus 1
Compartment
Synonyms
TLR3-mediated TICAM1-dependent activation of IRF3/IRF7, TLR3-mediated TRIF-dependent activation of IRF3/IRF7, Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon
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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
15502848 Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling

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

Nat Struct Mol Biol 2004
15210742 The roles of two IkappaB kinase-related kinases in lipopolysaccharide and

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

J Exp Med 2004
17332413 Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity

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

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

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

Proc Natl Acad Sci U S A 2004
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Event Information
Orthologous Events
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