IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR3

Stable Identifier
Reaction [binding]
Homo sapiens
Related Species
Influenza A virus, Rotavirus, Hepatitis B virus, Hepatitis C Virus, Human herpesvirus 1
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SH2-containing protein tyrosine phosphatase 2 (SHP-2) has been shown to inhibit the TRIF-dependent production of proinflammatory cytokines and type I interferon in LPS or poly(I-C)-stimulated mouse peritoneal macrophages. SHP-2 overexpression also inhibited TRIF-induced IFN-luciferase reporter gene expression in human embryonic kidney HEK293 cells. Experiments with truncated SHP-2 or truncated TBK1 mutants revealed that C-terminal domain of SHP-2 associates with N-terminal domain of TBK1 when coexpressed in HEK293 cells. Furthermore, SHP-2 is thought to prevent TBK1-mediated downstream substrate phosphorylation in tyrosine phosphatase activity independent manner by binding to kinase domain of TBK1 (An H et al. 2006). Two members of the interferon regulatory factor (IRF) family IRF3 and IRF7 are the major modulators of IFN gene expression (Hemmi H et al. 2004). Activation of IRF3 and IRF7, which is mediated by TBK1/IKK protein kinases, promotes IFN gene expression and the production of IFN developing an effective antiviral immune response (Hemmi H et al. 2004).

Irf-3 deficient mice were found to be more vulnerable to virus infection. Mouse cells defective in IRF3 and IRF7 expression totally fail to induce IFN genes in response to viral infection. It was shown on mice and mouse cells that both IRF3 and IRF7 have non redundant and distinct roles (Sato M et al. 2000). IRF3 is expressed at a basal level in normally growing cells and is a major factor in the early induction phase of IFN-alpha/beta production, while the IRF7 gene expression is induced upon IFNs stimulation and IRF7 is involved in the late induction phase.

Literature References
PubMed ID Title Journal Year
9566918 Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation

Hiscott, J, Lin, R, Pitha-Rowe, PM, Heylbroeck, C

Mol Cell Biol 1998
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
17157040 SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production

Zhang, Y, Cao, X, Zhao, W, Hou, J, Liu, S, Zheng, Y, Xie, Y, Yu, Y, Feng, G, An, H, Qian, C, Xu, H, Zhou, J

Immunity 2006
14703513 Identification of Ser-386 of interferon regulatory factor 3 as critical

Fujita, T, Inagaki, F, Takahashi, K, Yoneyama, M, Mori, M, Ito, T

J Biol Chem 2004
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