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Translational control of the innate immune response through IRF-7

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.

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Figure 1: Lack of 4E-BPs renders MEFs refractory to VSV replication.
Figure 2: Enhanced production of type-I IFN in 4E-BP1-/-4E-BP2-/- MEFs.
Figure 3: 4E-BP1-/-4E-BP2-/- mice are resistant to VSV infection.
Figure 4: 4E-BPs inhibit translation of Irf7 mRNA.
Figure 5: Reduction of IRF-7 in 4E-BP1-/-4E-BP2-/- MEFs renders the cells susceptible to VSV infection and blocks type-I IFN production.

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Acknowledgements

We thank M. Karin, M. Gale, R. Lin, W. Sossin, L. W. Ler and A. Rosenfeld for comments on the paper, and N. Taheri, A. Sylvestre and C. Lister for assistance. RIG-I and MDA5 antibodies were provided by H. Kato. This work was supported by a grant from the National Cancer Institute of Canada to N.S. and J.C.B. N.S. is a Howard Hughes Medical Institute (HHMI) International scholar. R.C. is supported by a Cole Foundation post-doctoral fellowship and R.J.O.D. is supported by a Terry Fox Foundation studentship.

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Correspondence to Mauro Costa-Mattioli or Nahum Sonenberg.

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Colina, R., Costa-Mattioli, M., Dowling, R. et al. Translational control of the innate immune response through IRF-7. Nature 452, 323–328 (2008). https://doi.org/10.1038/nature06730

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