RAIDD Mediates TLR3 and IRF7 Driven Type I Interferon Production

Cell Physiol Biochem. 2016;39(4):1271-80. doi: 10.1159/000447832. Epub 2016 Sep 8.


Background/aims: Viral infections represent a global health problem with the need for new viral therapies and better understanding of the immune response during infection. The most immediate and potent anti-viral defense mechanism is the production of type I interferon (IFN-I) which are activated rapidly following recognition of viral infection by host pathogen recognition receptors (PRR). The mechanisms of innate cellular signaling downstream of PRR activation remain to be fully understood. In the present study, we demonstrate that CASP2 and RIPK1 domain-containing adaptor with death domain (CRADD/RAIDD) is a critical component in type I IFN production.

Methods: The role of RAIDD during IFN-I production was investigated using western blot, shRNA mediated lentiviral knockdown, immunoprecipitation and IFN-I driven dual luciferase assay.

Results: Immunoprecipitation analysis revealed the molecular interaction of RAIDD with interferon regulatory factor 7 (IRF7) and its phosphorylating kinase IKKε. Using an IFN-4α driven dual luciferase analysis in RAIDD deficient cells, type I IFN activation by IKKε and IRF7 was dramatically reduced. Furthermore, deletion of either the caspase recruitment domain (CARD) or death domain (DD) of RAIDD inhibited IKKε and IRF7 mediated interferon-4α activation.

Conclusion: We have identified that the adaptor molecule RAIDD coordinates IKKε and IRF7 interaction to ensure efficient expression of type I interferon.

MeSH terms

  • Animals
  • CRADD Signaling Adaptor Protein / genetics*
  • CRADD Signaling Adaptor Protein / immunology
  • Caspase Activation and Recruitment Domain
  • Gene Expression Regulation
  • Genes, Reporter
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / genetics*
  • I-kappa B Kinase / immunology
  • Interferon Regulatory Factor-7 / genetics*
  • Interferon Regulatory Factor-7 / immunology
  • Interferon-alpha / genetics
  • Interferon-alpha / immunology
  • Interferon-beta / genetics
  • Interferon-beta / immunology
  • Lentivirus / genetics
  • Lentivirus / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mice
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Poly I-C / pharmacology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Signal Transduction
  • Toll-Like Receptor 3 / genetics*
  • Toll-Like Receptor 3 / immunology


  • CRADD Signaling Adaptor Protein
  • CRADD protein, human
  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • Interferon-alpha
  • Recombinant Proteins
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Interferon-beta
  • Luciferases
  • I-kappa B Kinase
  • Poly I-C