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OASL1 inhibits translation of the type I interferon–regulating transcription factor IRF7

Nature Immunology volume 14, pages 346–355 (2013)Cite this article

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A Corrigendum to this article was published on 19 July 2013

This article has been updated

Abstract

The production of type I interferon is essential for viral clearance but is kept under tight control to avoid unnecessary tissue damage from hyperinflammatory responses. Here we found that OASL1 inhibited translation of IRF7, the master transcription factor for type I interferon, and thus negatively regulated the robust production of type I interferon during viral infection. OASL1 inhibited the translation of IRF7 mRNA by binding to the 5′ untranslated region (UTR) of IRF7 and possibly by inhibiting scanning of the 43S preinitiation complex along the message. Oasl1−/− mice were resistant to viral infection because of the greater abundance of type I interferon, which suggests that OASL1 could be a potential therapeutic target for boosting the production of type I interferon during viral infection.

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Figure 1: Oasl1−/− BMDMs produce more type I interferon than do wild-type BMDMs after treatment with poly(I:C) and viral infection.
Figure 2: Oasl1−/− mice produce more type I interferon than do wild-type mice after poly(I:C) treatment and are more resistant to viral infection.
Figure 3: Oasl1−/− BMDMs produce more IRF7 protein than do wild-type BMDMs, but have an amount of IRF7 mRNA similar to that of wild-type BMDMs, after treatment with poly(I:C).
Figure 4: OASL1 specifically inhibits the translation of IRF7 mRNA in BMDMs.
Figure 5: The structured IRF7 5′ UTR is critical for OASL1-mediated inhibition of the translation of IRF7 in BMDMs.
Figure 6: The structured IRF7 5′ UTR is critical for OASL1-mediated inhibition of IRF7 translation in 293T cells.
Figure 7: OASL1 requires both the OAS and ubiquitin-like domains as well as three key residues in the OAS domain for full function.
Figure 8: OASL1 binds much more strongly to the IRF7 5′ UTR than to other RNA 5′ UTRs.

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  • 22 April 2013

    In the version of this article initially published, the second affiliation for Young-Joon Kim was missing. The correct affiliation includes the following: Department of Integrated Omics for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul, Republic of Korea. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    CAS  PubMed  Google Scholar 

  2. Lee, M.S. & Kim, Y.J. Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu. Rev. Biochem. 76, 447–480 (2007).

    CAS  PubMed  Google Scholar 

  3. Vallabhapurapu, S. & Karin, M. Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).

    CAS  PubMed  Google Scholar 

  4. Sato, M. et al. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction. Immunity 13, 539–548 (2000).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. Tamura, T., Yanai, H., Savitsky, D. & Taniguchi, T. The IRF family transcription factors in immunity and oncogenesis. Annu. Rev. Immunol. 26, 535–584 (2008).

    CAS  PubMed  Google Scholar 

  8. Wathelet, M.G. et al. Virus infection induces the assembly of coordinately activated transcription factors on the IFN-β enhancer in vivo. Mol. Cell 1, 507–518 (1998).

    CAS  PubMed  Google Scholar 

  9. Ning, S., Pagano, J.S. & Barber, G.N. IRF7: activation, regulation, modification and function. Genes Immun. 12, 399–414 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sato, M. et al. Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett. 441, 106–110 (1998).

    CAS  PubMed  Google Scholar 

  11. Stark, G.R., Kerr, I.M., Williams, B.R., Silverman, R.H. & Schreiber, R.D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    CAS  PubMed  Google Scholar 

  12. Silverman, R.H. Viral encounters with 2′,5′-oligoadenylate synthetase and RNase L during the interferon antiviral response. J. Virol. 81, 12720–12729 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kakuta, S., Shibata, S. & Iwakura, Y. Genomic structure of the mouse 2′,5′-oligoadenylate synthetase gene family. J. Interferon Cytokine Res. 22, 981–993 (2002).

    CAS  PubMed  Google Scholar 

  14. Kristiansen, H., Gad, H.H., Eskildsen-Larsen, S., Despres, P. & Hartmann, R. The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activities. J. Interferon Cytokine Res. 31, 41–47 (2011).

    CAS  PubMed  Google Scholar 

  15. Yan, W. et al. Mice deficient in oocyte-specific oligoadenylate synthetase-like protein OAS1D display reduced fertility. Mol. Cell Biol. 25, 4615–4624 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Mashimo, T. et al. A nonsense mutation in the gene encoding 2′-5′-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice. Proc. Natl. Acad. Sci. USA 99, 11311–11316 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Eskildsen, S., Justesen, J., Schierup, M.H. & Hartmann, R. Characterization of the 2′-5′-oligoadenylate synthetase ubiquitin-like family. Nucleic Acids Res. 31, 3166–3173 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Alexopoulou, L., Holt, A.C., Medzhitov, R. & Flavell, R.A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001).

    CAS  PubMed  Google Scholar 

  19. Unterholzner, L. et al. IFI16 is an innate immune sensor for intracellular DNA. Nat. Immunol. 11, 997–1004 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Gitlin, L. et al. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl. Acad. Sci. USA 103, 8459–8464 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Jung, A. et al. Lymphocytoid choriomeningitis virus activates plasmacytoid dendritic cells and induces a cytotoxic T-cell response via MyD88. J. Virol. 82, 196–206 (2008).

    CAS  PubMed  Google Scholar 

  23. Bonnefoy, F. et al. Plasmacytoid dendritic cells play a major role in apoptotic leukocyte-induced immune modulation. J. Immunol. 186, 5696–5705 (2011).

    CAS  PubMed  Google Scholar 

  24. Rose, S., Misharin, A. & Perlman, H. A novel Ly6C/Ly6G-based strategy to analyze the mouse splenic myeloid compartment. Cytometry A 81, 343–350 (2012).

    PubMed  Google Scholar 

  25. Kadeppagari, R.K., Sanchez, R.L. & Foster, T.P. HSV-2 inhibits type-I interferon signaling via multiple complementary and compensatory STAT2-associated mechanisms. Virus Res. 167, 273–284 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Herdy, B. et al. Translational control of the activation of transcription factor NF-κB and production of type I interferon by phosphorylation of the translation factor eIF4E. Nat. Immunol. 13, 543–550 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bachand, F. & Silver, P.A. PRMT3 is a ribosomal protein methyltransferase that affects the cellular levels of ribosomal subunits. EMBO J. 23, 2641–2650 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sonenberg, N. & Hinnebusch, A.G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731–745 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Komar, A.A. & Hatzoglou, M. Cellular IRES-mediated translation: the war of ITAFs in pathophysiological states. Cell Cycle 10, 229–240 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Schoggins, J.W. et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hiramatsu, N., Kasai, A., Hayakawa, K., Yao, J. & Kitamura, M. Real-time detection and continuous monitoring of ER stress in vitro and in vivo by ES-TRAP: evidence for systemic, transient ER stress during endotoxemia. Nucleic Acids Res. 34, e93 (2006).

    PubMed  PubMed Central  Google Scholar 

  32. Gruber, A.R., Lorenz, R., Bernhart, S.H., Neubock, R. & Hofacker, I.L. The Vienna RNA websuite. Nucleic Acids Res. 36, W70–W74 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. González-Navajas, J.M., Lee, J., David, M. & Raz, E. Immunomodulatory functions of type I interferons. Nat. Rev. Immunol. 12, 125–135 (2012).

    PubMed  PubMed Central  Google Scholar 

  34. Barbalat, R., Ewald, S.E., Mouchess, M.L. & Barton, G.M. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185–214 (2011).

    CAS  PubMed  Google Scholar 

  35. Hartmann, R., Justesen, J., Sarkar, S.N., Sen, G.C. & Yee, V.C. Crystal structure of the 2′-specific and double-stranded RNA-activated interferon-induced antiviral protein 2′-5′-oligoadenylate synthetase. Mol. Cell 12, 1173–1185 (2003).

    CAS  PubMed  Google Scholar 

  36. Wang, L., Jeng, K.S. & Lai, M.M. Poly(C)-binding protein 2 interacts with sequences required for viral replication in the hepatitis C virus (HCV) 5′ untranslated region and directs HCV RNA replication through circularizing the viral genome. J. Virol. 85, 7954–7964 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Muckenthaler, M.U., Galy, B. & Hentze, M.W. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu. Rev. Nutr. 28, 197–213 (2008).

    CAS  PubMed  Google Scholar 

  38. Richards, K.H. & Macdonald, A. Putting the brakes on the anti-viral response: negative regulators of type I interferon (IFN) production. Microbes Infect. 13, 291–302 (2011).

    CAS  PubMed  Google Scholar 

  39. Saitoh, T. et al. Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat. Immunol. 7, 598–605 (2006).

    CAS  PubMed  Google Scholar 

  40. Higgs, R. et al. Self protection from anti-viral responses–Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. PLoS ONE 5, e11776 (2010).

    PubMed  PubMed Central  Google Scholar 

  41. Colina, R. et al. Translational control of the innate immune response through IRF-7. Nature 452, 323–328 (2008).

    CAS  PubMed  Google Scholar 

  42. Marques, J. et al. The p59 oligoadenylate synthetase-like protein possesses antiviral activity that requires the C-terminal ubiquitin-like domain. J. Gen. Virol. 89, 2767–2772 (2008).

    CAS  PubMed  Google Scholar 

  43. Perelygin, A.A., Zharkikh, A.A., Scherbik, S.V. & Brinton, M.A. The mammalian 2′-5′ oligoadenylate synthetase gene family: evidence for concerted evolution of paralogous Oas1 genes in Rodentia and Artiodactyla. J. Mol. Evol. 63, 562–576 (2006).

    CAS  PubMed  Google Scholar 

  44. Lutz, M.B. et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999).

    CAS  PubMed  Google Scholar 

  45. Naik, S.H. et al. Cutting edge: generation of splenic CD8+ and CD8− dendritic cell equivalents in Fms-like tyrosine kinase 3 ligand bone marrow cultures. J. Immunol. 174, 6592–6597 (2005).

    CAS  PubMed  Google Scholar 

  46. Conner, D.A. Mouse embryo fibroblast (MEF) feeder cell preparation. Curr. Protoc. Mol. Biol. 51, 23.2.1–23.2.7 (2001).

    Google Scholar 

  47. Huang, W., Sherman, B.T. & Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).

    CAS  Google Scholar 

  48. Samarajiwa, S.A., Forster, S., Auchettl, K. & Hertzog, P.J. INTERFEROME: the database of interferon regulated genes. Nucleic Acids Res. 37, D852–D857 (2009).

    CAS  PubMed  Google Scholar 

  49. Smith, D.E. & Fisher, P.A. Identification, developmental regulation, and response to heat shock of two antigenically related forms of a major nuclear envelope protein in Drosophila embryos: application of an improved method for affinity purification of antibodies using polypeptides immobilized on nitrocellulose blots. J. Cell Biol. 99, 20–28 (1984).

    CAS  PubMed  Google Scholar 

  50. Morin, B. et al. High yield synthesis, purification and characterisation of the RNase L activators 5′-triphosphate 2′-5′-oligoadenylates. Antiviral Res. 87, 345–352 (2010).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S. Park and Y. Seo for technical support in the microinjection of embryonic stem cells; J. Ahn and H. Jung for technical help in mouse maintenance; J. Kang and Q. Zhang for technical help in the molecular studies; and G. Dranoff (Harvard Medical School) for the melanoma cell lines B16-FLT3L and B16-GM-CSF. Supported by the Global Research Laboratory program of the Ministry of Education, Science and Technology of Korea (MEST; K20704000006-10A0500-00610 to Y.-J.K.), the World Class University program funded by the Korean government (MEST) through the National Research Foundation of Korea (R312010000100860 to Y.-J.K.), the National Research Foundation of Korea funded by the Korean government (MEST; 2012028272 to Y.-J.K.) and the Korea Genetically Engineered Mouse Center Program of the National Research Foundation of the Korean government (MEST; 2011-0020603 to G.T.O.).

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  1. Myeong Sup Lee and Byungil Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea

    Myeong Sup Lee, Byungil Kim & Young-Joon Kim

  2. Division of Life and Pharmaceutical Sciences, Ewha Women's University, Seoul, Republic of Korea

    Goo Taeg Oh

  3. Department of Integrated Omics for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul, Republic of Korea

    Young-Joon Kim

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Contributions

M.S.L. and Y.-J.K. designed the project; M.S.L. and B.K. did the experiments; M.S.L., B.K. and Y.-J.K. wrote the paper; and G.T.O. managed the generation of the Oasl1-deficient mice from targeted embryonic stem cells.

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Correspondence to Young-Joon Kim.

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Lee, M., Kim, B., Oh, G. et al. OASL1 inhibits translation of the type I interferon–regulating transcription factor IRF7. Nat Immunol 14, 346–355 (2013). https://doi.org/10.1038/ni.2535

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