Pellino1 is required for interferon production by viral double-stranded RNA.
Viral double-stranded RNA, a ligand for Toll-like Receptor 3 (TLR3) and the cytoplasmic RNA receptors RIG1 and MDA5, activate a signaling network in which the IKK-related protein kinase TBK1 phosphorylates the transcription factor Interferon Regulatory Factor 3 (IRF3) and the E3 ubiquitin ligase Pellino1. IRF3 then translocates to the nucleus where it stimulates transcription of the interferonβ (IFNβ) gene, but the function of Pellino1 in this pathway is unknown. Here, we report that myeloid cells and embryonic fibroblasts from knock-in mice expressing an E3 ligase-deficient mutant of Pellino1 produce reduced levels of IFNβ mRNA and secrete much less IFNβ in response to viral double-stranded RNA because the interaction of IRF3 with the IFNβ promoter is impaired. These results identify Pellino1 as a novel component of the signal transduction network by which viral double-stranded RNA stimulates IFNβ gene transcription.
MRC Protein Phosphorylation Unit, University of Dundee, DD15EH, United Kingdom.
Karine
K
Enesa
Alban
A
Ordureau
Hilary
H
Smith
David
D
Barford
Peter C F
PC
Cheung
Janet
J
Patterson-Kane
J Simon C
JS
Arthur
Philip
P
Cohen
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D044767:Ubiquitin-Protein Ligases
D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D009687:Nuclear Proteins; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D012367:RNA, Viral; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D044767:Ubiquitin-Protein Ligases; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; C418046:Peli1 protein, mouse