A20 is a negative regulator of IFN regulatory factor 3 signaling

J Immunol. 2005 Feb 1;174(3):1507-12. doi: 10.4049/jimmunol.174.3.1507.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Dimerization
  • Down-Regulation
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Interferon Regulatory Factor-3
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / antagonists & inhibitors
  • Newcastle disease virus / immunology
  • Nuclear Proteins
  • Protein Serine-Threonine Kinases / metabolism
  • Proteins / antagonists & inhibitors
  • Proteins / genetics
  • Proteins / metabolism
  • Proteins / physiology*
  • RNA, Small Interfering / biosynthesis
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Receptors, Cell Surface / antagonists & inhibitors
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Repressor Proteins / physiology*
  • Response Elements / physiology
  • Signal Transduction* / immunology
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcriptional Activation
  • Transfection
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • DNA-Binding Proteins
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Nuclear Proteins
  • Proteins
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Repressor Proteins
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • Transcription Factors
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3