Translational control of the innate immune response through IRF-7

Transcriptional activation of cytokines, such as type-I interferons ( interferon ( IFN)- alpha and IFN- beta), 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- BP1 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.