RAIDD Mediates TLR3 and IRF7 Driven Type I Interferon Production.
OBJECTIVE
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.


CONCLUSIONS
We have identified that the adaptor molecule RAIDD coordinates IKKε and IRF7 interaction to ensure efficient expression of type I interferon.
Institute of Molecular Medicine II, Heinrich Heine University, Düsseldorf, Germany.
Sathish Kumar
SK
Maney
Haifeng C
HC
Xu
Jun
J
Huang
Aleksandra A
AA
Pandyra
Christian
C
Ehlting
Renan
R
Aguilar-Valenzuela
Vitaly I
VI
Pozdeev
David R
DR
McIlwain
Albert
A
Zimmermann
Johannes G
JG
Bode
Hartmut
H
Hengel
Carsten J
CJ
Kirschning
Ira R
IR
Kim
John
J
Hiscott
Dirk
D
Brenner
Dieter
D
Häussinger
Pamela S
PS
Ohashi
Tak W
TW
Mak
Karl S
KS
Lang
Philipp A
PA
Lang
D000818:Animals; D053420:CRADD Signaling Adaptor Protein / Q000235:genetics* / Q000276:immunology; D000071476:Caspase Activation and Recruitment Domain; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000235:genetics* / Q000276:immunology; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics* / Q000276:immunology
D053420:CRADD Signaling Adaptor Protein; C104252:CRADD protein, human; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D011994:Recombinant Proteins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D008156:Luciferases; D051550:I-kappa B Kinase; D011070:Poly I-C