The Interferon Regulatory Factor, IRF5, Is a Central Mediator of Toll-like Receptor 7 Signaling

• Published in: The Journal of biological chemistry Vol. 280; no. 17; pp. 17005 - 17012
• Main Authors: Schoenemeyer, Annett, Barnes, Betsy J., Mancl, Margo.E., Latz, Eicke, Goutagny, Nadege, Pitha, Paula M., Fitzgerald, Katherine A., Golenbock, Douglas T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.04.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Signal Transducing; Antigens, Differentiation - metabolism; Biological Assay; Cell Line; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Dose-Response Relationship, Drug; Electroporation; Genes, Reporter; Glutathione Transferase - metabolism; Humans; Interferon Regulatory Factor-3; Interferon Regulatory Factor-7; Interferon Regulatory Factors; Interferon Type I - metabolism; Ligands; Lipopolysaccharides - metabolism; Membrane Glycoproteins - metabolism; Microscopy, Confocal; Models, Biological; Myeloid Differentiation Factor 88; Phosphorylation; Receptors, Cell Surface - metabolism; Receptors, Immunologic - metabolism; Recombinant Fusion Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Double-Stranded - metabolism; RNA, Small Interfering - metabolism; Signal Transduction; Time Factors; Toll-Like Receptor 3; Toll-Like Receptor 4; Toll-Like Receptor 7; Toll-Like Receptor 8; Toll-Like Receptors; Transcription Factors - metabolism; Transcription Factors - physiology; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M412584200

Interferon regulatory factors (IRFs) are critical components of virus-induced immune activation and type I interferon regulation. IRF3 and IRF7 are activated in response to a variety of viruses or after engagement of Toll-like receptor (TLR) 3 and TLR4 by double-stranded RNA and lipopolysaccharide, respectively. The activation of IRF5, is much more restricted. Here we show that in contrast to IRF3 and IRF7, IRF5 is not a target of the TLR3 signaling pathway but is activated by TLR7 or TLR8 signaling. We also demonstrate that MyD88, interleukin 1 receptor-associated kinase 1, and tumor necrosis factor receptor-associated factor 6 are required for the activation of IRF5 and IRF7 in the TLR7 signaling pathway. Moreover, ectopic expression of IRF5 enabled type I interferon production in response to TLR7 signaling, whereas knockdown of IRF5 by small interfering RNA reduced type I interferon induction in response to the TLR7 ligand, R-848. IRF5 and IRF7, therefore, emerge from these studies as critical mediators of TLR7 signaling.