TICAM1-dependent activation of IRF3/IRF7

Stable Identifier
Homo sapiens
Related Species
Influenza A virus, Rotavirus, Hepatitis B virus, Hepatitis C Virus, Human herpesvirus 1
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
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this pathway in the Pathway Browser
Cell stimulation with viral double-stranded (ds) RNA and bacterial lipopolysaccharide (LPS) activate Toll-like receptors 3 (TLR3) and TLR4, respectively, triggering the activation the activation of two IKK-related serine/threonine kinases, TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε, IKBKE) which directly phosphorylate interferon regulatory factor 3 (IRF3) and IRF7 promoting their dimerization and translocation into the nucleus. Although both kinases show structural and functional similarities, it seems that TBK1 and IKBKE differ in their regulation of downstream signaling events of TLR3/TLR4.

IRF3 activation and interferon β (IFNβ) production by poly(I:C), a synthetic analog of dsRNA, are decreased in TBK1-deficient mouse fibroblasts, whereas normal activation was observed in the IKBKE-deficient fibroblasts. However, in double-deficient mouse fibroblasts, the activation of IRF3 is completely abolished, suggesting a partially redundant functions of TBK1 and IKKε (IKBKE) (Hemmi H et al., 2004).

The poly(I:C)-induced phosphorylation of TBK1 and IRF3 was abolished in TRIF (TICAM1)-knockout human keratinocyte HACAT cells (Bakshi S et al., 2017). TICAM1 is utilized as an adaptor protein by TLR3 and TLR4 (Yamamoto M et al., 2003).

TLR3 recruits and activates PI3 kinase (PI3K), which activates the downstream kinase, Akt, leading to full phosphorylation and activation of IRF3 (Sarkar SN et al., 2004). When PI3K is not recruited to TLR3 or its activity is blocked, IRF3 is only partially phosphorylated and fails to bind the promoter of the target gene (Sarkar SN et al., 2004).

Literature References
PubMed ID Title Journal Year
15210742 The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection

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
Event Information
Orthologous Events
Cite Us!