A20 is a negative regulator of IFN regulatory factor 3 signaling.
IFN regulatory factor 3 (IRF-3) is a critical transcription factor that regulates an establishment of innate immune status following detection of viral pathogens. Recent studies have revealed that two IkappaB kinase (IKK)-like kinases, NF-kappaB-activating kinase/Traf family member-associated NF-kappaB activator-binding kinase 1 and IKK-i/IKKepsilon, are responsible for activation of IRF-3, but ... the regulatory mechanism of the IRF-3 signaling pathway has not been fully understood. In this study, we report that IRF-3 activation is suppressed by A20, which was initially identified as an inhibitor of apoptosis and inducibly expressed by dsRNA. A20 physically interacts with NF-kappaB-activating kinase/Traf family member-associated NF-kappaB activator-binding kinase 1 and IKK-i/IKKepsilon, and inhibits dimerization of IRF-3 following engagement of TLR3 by dsRNA or Newcastle disease virus infection, leading to suppression of the IFN stimulation response element- and IFN-beta promoter-dependent transcription. Importantly, knocking down of A20 expression by RNA interference results in enhanced IRF-3-dependent transcription triggered by the stimulation of TLR3 or virus infection. Our study thus demonstrates that A20 is a candidate negative regulator of the signaling cascade to IRF-3 activation in the innate antiviral response.
Mesh Terms:
Cell Line, DNA-Binding Proteins, Dimerization, Down-Regulation, HeLa Cells, Humans, I-kappa B Kinase, Interferon Regulatory Factor-3, Intracellular Signaling Peptides and Proteins, Membrane Glycoproteins, Newcastle disease virus, Nuclear Proteins, Protein-Serine-Threonine Kinases, Proteins, RNA, Small Interfering, Receptors, Cell Surface, Repressor Proteins, Response Elements, Signal Transduction, Toll-Like Receptor 3, Toll-Like Receptors, Transcription Factors, Transcriptional Activation, Transfection, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Cell Line, DNA-Binding Proteins, Dimerization, Down-Regulation, HeLa Cells, Humans, I-kappa B Kinase, Interferon Regulatory Factor-3, Intracellular Signaling Peptides and Proteins, Membrane Glycoproteins, Newcastle disease virus, Nuclear Proteins, Protein-Serine-Threonine Kinases, Proteins, RNA, Small Interfering, Receptors, Cell Surface, Repressor Proteins, Response Elements, Signal Transduction, Toll-Like Receptor 3, Toll-Like Receptors, Transcription Factors, Transcriptional Activation, Transfection, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
J. Immunol.
Date: Feb. 01, 2005
PubMed ID: 15661910
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