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Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression

Nature Immunology volume 11, pages 725–733 (2010)Cite this article

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Abstract

The molecular mechanism by which roquin controls the expression of inducible costimulator (ICOS) to prevent autoimmunity remains unsolved. Here we show that in helper T cells, roquin localized to processing (P) bodies and downregulated ICOS expression. The repression was dependent on the RNA helicase Rck, and roquin interacted with Rck and the enhancer of decapping Edc4, which act together in mRNA decapping. Sequences in roquin that confer P-body localization were essential for roquin-mediated ICOS repression. However, this process did not require microRNAs or the RNA-induced silencing complex (RISC). Instead, roquin bound ICOS mRNA directly, showing an intrinsic preference for a previously unrecognized sequence in the 3′ untranslated region (3′ UTR). Our results support a model in which roquin controls ICOS expression through binding to the 3′ UTR of ICOS mRNA and by interacting with proteins that confer post-transcriptional repression.

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Figure 1: ICOS expression is placed under the control of roquin in differentiated helper T cells.
Figure 2: Carboxy-terminal sequences in roquin are required for ICOS repression and roquin localization.
Figure 3: Roquin-mediated repression of ICOS correlates with P-body localization independently of TIA-1.
Figure 4: Roquin protein is associated with Rck and Edc4 and shows functional dependence on Rck expression.
Figure 5: Roquin-mediated ICOS repression does not depend on miRNAs or miRISC formation.
Figure 6: Roquin binds to ICOS mRNA through its ROQ and zinc-finger domains.
Figure 7: Roquin binds to ICOS mRNA with an intrinsic 'preference' for a specific region in the 3′ UTR.

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References

  1. Yu, D. et al. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450, 299–303 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Vinuesa, C.G. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Anderson, P., Phillips, K., Stoecklin, G. & Kedersha, N. Post-transcriptional regulation of proinflammatory proteins. J. Leukoc. Biol. 76, 42–47 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Hao, S. & Baltimore, D. The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules. Nat. Immunol. 10, 281–288 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hoefig, K.P. & Heissmeyer, V. MicroRNAs grow up in the immune system. Curr. Opin. Immunol. 20, 281–287 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Stefl, R., Skrisovska, L. & Allain, F.H. RNA sequence- and shape-dependent recognition by proteins in the ribonucleoprotein particle. EMBO Rep. 6, 33–38 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jing, Q. et al. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120, 623–634 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Kedde, M. et al. RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 131, 1273–1286 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Vasudevan, S. & Steitz, J.A. AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell 128, 1105–1118 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tan, A.H., Wong, S.C. & Lam, K.P. Regulation of mouse inducible costimulator (ICOS) expression by Fyn-NFATc2 and ERK signaling in T cells. J. Biol. Chem. 281, 28666–28678 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Bossaller, L. et al. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J. Immunol. 177, 4927–4932 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Dong, C. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409, 97–101 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Dong, C., Temann, U.A. & Flavell, R.A. Cutting edge: critical role of inducible costimulator in germinal center reactions. J. Immunol. 166, 3659–3662 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. McAdam, A.J. et al. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J. Immunol. 165, 5035–5040 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Tafuri, A. et al. ICOS is essential for effective T-helper-cell responses. Nature 409, 105–109 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Linterman, M.A. et al. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206, 561–576 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wan, Y.Y. et al. Transgenic expression of the coxsackie/adenovirus receptor enables adenoviral-mediated gene delivery in naive T cells. Proc. Natl. Acad. Sci. USA 97, 13784–13789 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Oberdoerffer, P. et al. Efficiency of RNA interference in the mouse hematopoietic system varies between cell types and developmental stages. Mol. Cell. Biol. 25, 3896–3905 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Heissmeyer, V., Ansel, K.M. & Rao, A. A plague of autoantibodies. Nat. Immunol. 6, 642–644 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Chu, C.Y. & Rana, T.M. Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS Biol. 4, e210 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Didiot, M.C., Subramanian, M., Flatter, E., Mandel, J.L. & Moine, H. Cells lacking the fragile X mental retardation protein (FMRP) have normal RISC activity but exhibit altered stress granule assembly. Mol. Biol. Cell 20, 428–437 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mazroui, R. et al. Trapping of messenger RNA by fragile X mental retardation protein into cytoplasmic granules induces translation repression. Hum. Mol. Genet. 11, 3007–3017 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Franks, T.M. & Lykke-Andersen, J. The control of mRNA decapping and P-body formation. Mol. Cell 32, 605–615 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Michelitsch, M.D. & Weissman, J.S. A census of glutamine/asparagine-rich regions: implications for their conserved function and the prediction of novel prions. Proc. Natl. Acad. Sci. USA 97, 11910–11915 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reijns, M.A., Alexander, R.D., Spiller, M.P. & Beggs, J.D. A role for Q/N-rich aggregation-prone regions in P-body localization. J. Cell Sci. 121, 2463–2472 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Gilks, N. et al. Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol. Biol. Cell 15, 5383–5398 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Parameswaran, P. et al. Six RNA viruses and forty-one hosts: viral small RNAs and modulation of small RNA repertoires in vertebrate and invertebrate systems. PLoS Pathog. 6, e1000764 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Yekta, S., Tabin, C.J. & Bartel, D.P. MicroRNAs in the Hox network: an apparent link to posterior prevalence. Nat. Rev. Genet. 9, 789–796 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Su, H., Trombly, M.I., Chen, J. & Wang, X. Essential and overlapping functions for mammalian Argonautes in microRNA silencing. Genes Dev. 23, 304–317 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Athanasopoulos, V. et al. The ROQUIN family of proteins localizes to stress granules via the ROQ domain and binds target mRNAs. FEBS J. 277, 2109–2127 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Scheu, S. et al. Activation of the integrated stress response during T helper cell differentiation. Nat. Immunol. 7, 644–651 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Cougot, N., van Dijk, E., Babajko, S. & Seraphin, B. 'Cap-tabolism'. Trends Biochem. Sci. 29, 436–444 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Eulalio, A., Behm-Ansmant, I. & Izaurralde, E. P bodies: at the crossroads of post-transcriptional pathways. Nat. Rev. Mol. Cell Biol. 8, 9–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Parker, R. & Sheth, U. P bodies and the control of mRNA translation and degradation. Mol. Cell 25, 635–646 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Lunde, B.M., Moore, C. & Varani, G. RNA-binding proteins: modular design for efficient function. Nat. Rev. Mol. Cell Biol. 8, 479–490 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Weinmann, L. et al. Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Cell 136, 496–507 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. Schmidt-Supprian and D. Niessing for critical reading of the manuscript and discussions; G. Stoecklin for unpublished observations and advice; C. Vinuesa (The John Curtin School of Medical Research, Canberra, Australia) for ICOS and roquin cDNA; G. Hannon (Cold Spring Harbor Laboratory) for Dicer1fl/+ mice; C. Wilson (University of Washington) for Tg(Cd4-cre) mice; N. Kedersha and P. Anderson (Brigham and Women's Hospital) for TIA-1-knockout MEFs; U. Fischer (Biozentrum Würzburg) for anti-FMRP; H. Sarioglu for mass-spectrometry analysis; and C. Thirion and L. Behrend (Sirion Biotech) for advice and reagents for adenoviral infection. Supported by Deutsche Forschungsgemeinschaft (SFB 571 to V.H.) and Fritz Thyssen Foundation (V.H.).

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Author notes

  1. Kai P Hoefig and Katharina U Vogel: These authors contributed equally to this work.

Authors and Affiliations

  1. Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Molecular Immunology, Munich, Germany

    Elke Glasmacher, Kai P Hoefig, Katharina U Vogel, Nicola Rath, Lirui Du, Christine Wolf, Elisabeth Kremmer & Vigo Heissmeyer

  2. Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois, USA

    Xiaozhong Wang

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Contributions

E.G. did most experiments, with the help of K.P.H., N.R. and C.W.; K.U.V. contributed to some experiments and edited the manuscript; L.D., E.K. and X.W. established tools and provided advice; E.G. and V.H. planned the project together; and V.H. supervised the experiments and wrote the manuscript.

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Correspondence to Vigo Heissmeyer.

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Glasmacher, E., Hoefig, K., Vogel, K. et al. Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nat Immunol 11, 725–733 (2010). https://doi.org/10.1038/ni.1902

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