Translational control of the innate immune response through IRF-7

Rodney Colina, Mauro Costa-Mattioli (), Ryan J. O. Dowling, Maritza Jaramillo, Lee-Hwa Tai, Caroline J. Breitbach, Yvan Martineau, Ola Larsson, Liwei Rong, Yuri V. Svitkin, Andrew P. Makrigiannis, John C. Bell and Nahum Sonenberg ()
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Rodney Colina: McGill University, Montreal, Quebec H3G 1Y6, Canada
Mauro Costa-Mattioli: McGill University, Montreal, Quebec H3G 1Y6, Canada
Ryan J. O. Dowling: McGill University, Montreal, Quebec H3G 1Y6, Canada
Maritza Jaramillo: McGill University, Montreal, Quebec H3G 1Y6, Canada
Lee-Hwa Tai: Institut de Recherches Cliniques de Montréal, Laboratory of Molecular Immunology, Université de Montréal, Montréal, Quebec H2W 1R7, Canada
Caroline J. Breitbach: Ottawa Health Research Institute, Ottawa, Ontario K1H 8L6, Canada
Yvan Martineau: McGill University, Montreal, Quebec H3G 1Y6, Canada
Ola Larsson: McGill University, Montreal, Quebec H3G 1Y6, Canada
Liwei Rong: McGill University, Montreal, Quebec H3G 1Y6, Canada
Yuri V. Svitkin: McGill University, Montreal, Quebec H3G 1Y6, Canada
Andrew P. Makrigiannis: Institut de Recherches Cliniques de Montréal, Laboratory of Molecular Immunology, Université de Montréal, Montréal, Quebec H2W 1R7, Canada
John C. Bell: Ottawa Health Research Institute, Ottawa, Ontario K1H 8L6, Canada
Nahum Sonenberg: McGill University, Montreal, Quebec H3G 1Y6, Canada

Nature, 2008, vol. 452, issue 7185, 323-328

Abstract: Abstract Transcriptional activation of cytokines, such as type-I interferons (interferon (IFN)-α and IFN-β), constitutes the first line of antiviral defence. Here we show that translational control is critical for induction of type-I IFN production. In mouse embryonic fibroblasts lacking the translational repressors 4E-BP1 and 4E-BP2, the threshold for eliciting type-I IFN production is lowered. Consequently, replication of encephalomyocarditis virus, vesicular stomatitis virus, influenza virus and Sindbis virus is markedly suppressed. Furthermore, mice with both 4E- and 4E-BP2 genes (also known as Eif4ebp1 and Eif4ebp2, respectively) knocked out are resistant to vesicular stomatitis virus infection, and this correlates with an enhanced type-I IFN production in plasmacytoid dendritic cells and the expression of IFN-regulated genes in the lungs. The enhanced type-I IFN response in 4E-BP1-/- 4E-BP2-/- double knockout mouse embryonic fibroblasts is caused by upregulation of interferon regulatory factor 7 (Irf7) messenger RNA translation. These findings highlight the role of 4E-BPs as negative regulators of type-I IFN production, via translational repression of Irf7 mRNA.

Date: 2008
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DOI: 10.1038/nature06730

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