1. Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec H3G 1Y6, Canada
2. Institut de Recherches Cliniques de Montréal, Laboratory of Molecular Immunology, Université de Montréal, Montréal, Quebec H2W 1R7, Canada
3. Ottawa Health Research Institute, Ottawa, Ontario K1H 8L6, Canada
4. These authors contributed equally to this work.

Correspondence to: Mauro Costa-Mattioli^1,4Nahum Sonenberg¹ Correspondence and requests for materials should be addressed to N.S. (Email: nahum.sonenberg@mcgill.ca) or M.C.-M. (Email: mauro.costa-mattioli@mail.mcgill.ca).

Abstract

Transcriptional activation of cytokines, such as type-I interferons (interferon (IFN)- and IFN-), 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.

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