Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Garcia-Sastre, A. & Biron, C. A. Type 1 interferons and the virus-host relationship: a lesson in detente. Science 312, 879–882 (2006)

    Article  ADS  CAS  Google Scholar 

  2. Katze, M. G., He, Y. & Gale, M. Viruses and interferon: a fight for supremacy. Nature Rev. Immunol. 2, 675–687 (2002)

    Article  CAS  Google Scholar 

  3. Kawai, T. & Akira, S. Innate immune recognition of viral infection. Nature Immunol. 7, 131–137 (2006)

    Article  CAS  Google Scholar 

  4. Meylan, E., Tschopp, J. & Karin, M. Intracellular pattern recognition receptors in the host response. Nature 442, 39–44 (2006)

    Article  ADS  CAS  Google Scholar 

  5. Mathews, M. B., Sonenberg, N. & Hershey, J. W. B. Origins and principles of translational control. In Translational Control in Biology and Medicine (eds Mathews, M. B., Sonenberg, N. & Hershey, J. W. B.) 1–40 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2007)

    Google Scholar 

  6. Shatkin, A. J. mRNA cap binding proteins: essential factors for initiating translation. Cell 40, 223–224 (1985)

    Article  CAS  Google Scholar 

  7. Gingras, A. C., Raught, B. & Sonenberg, N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68, 913–963 (1999)

    Article  CAS  Google Scholar 

  8. Sonenberg, N., Morgan, M. A., Merrick, W. C. & Shatkin, A. J. A polypeptide in eukaryotic initiation factors that crosslinks specifically to the 5′-terminal cap in mRNA. Proc. Natl Acad. Sci. USA 75, 4843–4847 (1978)

    Article  ADS  CAS  Google Scholar 

  9. Rozen, F. et al. Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F. Mol. Cell. Biol. 10, 1134–1144 (1990)

    Article  CAS  Google Scholar 

  10. Pestova, T. V., Lorsch, J. R. & Hellen, C. U. T. In Translational Control in Biology and Medicine (eds Mathews, M. B., Sonenberg, N. & Hershey, J. W. B.) 87–128 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2007)

    Google Scholar 

  11. Pause, A. et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature 371, 762–767 (1994)

    Article  ADS  CAS  Google Scholar 

  12. Poulin, F., Gingras, A. C., Olsen, H., Chevalier, S. & Sonenberg, N. 4E–BP3, a new member of the eukaryotic initiation factor 4E-binding protein family. J. Biol. Chem. 273, 14002–14007 (1998)

    Article  CAS  Google Scholar 

  13. Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945 (2004)

    Article  CAS  Google Scholar 

  14. Mohr, I. J., Pe'ery, T. & Mathews, M. B. Protein synthesis and translational control during viral infection. In Translational Control in Biology and Medicine (eds Mathews, M. B., Sonenberg, N. & Hershey, J. W. B.) 545–600 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2007)

    Google Scholar 

  15. Le Bacquer, O. et al. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E–BP1 and 4E–BP2. J. Clin. Invest. 117, 387–396 (2007)

    Article  CAS  Google Scholar 

  16. Poulin, F., Brueschke, A. & Sonenberg, N. Gene fusion and overlapping reading frames in the mammalian genes for 4E–BP3 and MASK. J. Biol. Chem. 278, 52290–52297 (2003)

    Article  CAS  Google Scholar 

  17. Belkowski, L. S. & Sen, G. C. Inhibition of vesicular stomatitis viral mRNA synthesis by interferons. J. Virol. 61, 653–660 (1987)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Colonna, M., Trinchieri, G. & Liu, Y. J. Plasmacytoid dendritic cells in immunity. Nature Immunol. 5, 1219–1226 (2004)

    Article  CAS  Google Scholar 

  19. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005)

    Article  ADS  CAS  Google Scholar 

  20. Koromilas, A. E., Lazaris-Karatzas, A. & Sonenberg, N. mRNAs containing extensive secondary structure in their 5′ non-coding region translate efficiently in cells overexpressing initiation factor eIF-4E. EMBO J. 11, 4153–4158 (1992)

    Article  CAS  Google Scholar 

  21. Honda, K., Takaoka, A. & Taniguchi, T. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 25, 349–360 (2006)

    Article  CAS  Google Scholar 

  22. Stetson, D. B. & Medzhitov, R. Type I interferons in host defense. Immunity 25, 373–381 (2006)

    Article  CAS  Google Scholar 

  23. Durbin, J. E., Hackenmiller, R., Simon, M. C. & Levy, D. E. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84, 443–450 (1996)

    Article  CAS  Google Scholar 

  24. Meraz, M. A. et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84, 431–442 (1996)

    Article  CAS  Google Scholar 

  25. Park, C., Li, S., Cha, E. & Schindler, C. Immune response in Stat2 knockout mice. Immunity 13, 795–804 (2000)

    Article  CAS  Google Scholar 

  26. Zhou, A. et al. Interferon action and apoptosis are defective in mice devoid of 2′,5′-oligoadenylate-dependent RNase L. EMBO J. 16, 6355–6363 (1997)

    Article  CAS  Google Scholar 

  27. Kato, H. et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23, 19–28 (2005)

    Article  CAS  Google Scholar 

  28. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006)

    Article  ADS  CAS  Google Scholar 

  29. Kaur, S. et al. Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling. J. Biol. Chem. 282, 1757–1768 (2007)

    Article  CAS  Google Scholar 

  30. Sarkar, S. N. et al. Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling. Nature Struct. Mol. Biol. 11, 1060–1067 (2004)

    Article  CAS  Google Scholar 

  31. Vanhaesebroeck, B., Ali, K., Bilancio, A., Geering, B. & Foukas, L. C. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem. Sci. 30, 194–204 (2005)

    Article  CAS  Google Scholar 

  32. Sen, G. C. & Sarkar, S. N. Transcriptional signaling by double-stranded RNA: role of TLR3. Cytokine Growth Factor Rev. 16, 1–14 (2005)

    Article  CAS  Google Scholar 

  33. Hiscott, J. et al. Convergence of the NF-κB and interferon signaling pathways in the regulation of antiviral defense and apoptosis. Ann. NY Acad. Sci. 1010, 237–248 (2003)

    Article  ADS  CAS  Google Scholar 

  34. Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nature Rev. Immunol. 6, 644–658 (2006)

    Article  CAS  Google Scholar 

  35. Todaro, G. J. & Green, H. Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J. Cell Biol. 17, 299–313 (1963)

    Article  CAS  Google Scholar 

  36. Costa-Mattioli, M., Svitkin, Y. & Sonenberg, N. La autoantigen is necessary for optimal function of the poliovirus and hepatitis C virus internal ribosome entry site in vivo and in vitro. Mol. Cell. Biol. 24, 6861–6870 (2004)

    Article  CAS  Google Scholar 

  37. Berlanga, J. J. et al. Antiviral effect of the mammalian translation initiation factor 2α kinase GCN2 against RNA viruses. EMBO J. 25, 1730–1740 (2006)

    Article  CAS  Google Scholar 

  38. Stojdl, D. F. et al. The murine double-stranded RNA-dependent protein kinase PKR is required for resistance to vesicular stomatitis virus. J. Virol. 74, 9580–9585 (2000)

    Article  CAS  Google Scholar 

  39. Costa-Mattioli, M. et al. eIF2α phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129, 195–206 (2007)

    Article  CAS  Google Scholar 

  40. Stojdl, D. F. et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nature Med. 6, 821–825 (2000)

    Article  CAS  Google Scholar 

  41. Irizarry, R. A. et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31, e15 (2003)

    Article  Google Scholar 

  42. Dai, M. et al. Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res. 33, e175 (2005)

    Article  Google Scholar 

  43. Sandberg, R. & Larsson, O. Improved precision and accuracy for microarrays using updated probe set definitions. BMC Bioinformatics 8, 48 (2007)

    Article  Google Scholar 

  44. Gene Ontology Consortium The Gene Ontology (GO) project in 2006. Nucleic Acids Res. 34, D322–D326 (2006)

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Mauro Costa-Mattioli or Nahum Sonenberg.

Supplementary information

Supplementary Information

The file contains Supplementary Figures S1-S10 with Legends. (PDF 1569 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06730

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing