Abstract
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- 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Cycle Proteins
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Cells, Cultured
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Dendritic Cells / immunology
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Embryo, Mammalian / cytology
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Eukaryotic Initiation Factors / deficiency
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Eukaryotic Initiation Factors / genetics
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Eukaryotic Initiation Factors / metabolism
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Fibroblasts / virology
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Gene Deletion
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Immunity, Innate / genetics
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Immunity, Innate / immunology*
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Interferon Regulatory Factor-7 / biosynthesis*
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Interferon Regulatory Factor-7 / genetics
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Interferon Regulatory Factor-7 / metabolism
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Interferon Type I / biosynthesis
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Interferon Type I / immunology
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Mice
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Mice, Knockout
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Phosphoproteins / deficiency
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Biosynthesis*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Vesicular stomatitis Indiana virus / physiology
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Virus Physiological Phenomena
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Virus Replication
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cell Cycle Proteins
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Eif4ebp1 protein, mouse
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Eif4ebp2 protein, mouse
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Eukaryotic Initiation Factors
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Interferon Regulatory Factor-7
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Interferon Type I
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Phosphoproteins
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RNA, Messenger