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The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance

Nature Immunology volume 16, pages 737–745 (2015)Cite this article

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Abstract

Aire is a transcriptional regulator that induces the promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for the induction of immunological self-tolerance. Studies have offered molecular insights into how Aire operates, but more comprehensive understanding of this process still remains elusive. Here we found abundant expression of the protein deacetylase Sirtuin-1 (Sirt1) in mature Aire+ mTECs, wherein it was required for the expression of Aire-dependent TRA-encoding genes and the subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and identifies a unique function for Sirt1 in preventing organ-specific autoimmunity.

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Figure 1: mTECs are the main Sirt1-expressing cells in the immune system.
Figure 2: Sirt1 expression correlates with Aire expression but is Aire independent.
Figure 3: Sirt1 is essential for Aire-driven expression of TRA-encoding genes in vivo.
Figure 4: Sirt1 physically associates with Aire and induces its deacetylation.
Figure 5: Deacetylation of Aire is required for its transcriptional ability.
Figure 6: Sirt1 deficiency resembles Aire-linked organ-specific autoimmunity.

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References

  1. Rodewald, H.-R. Thymus organogenesis. Annu. Rev. Immunol. 26, 355–388 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Anderson, G. & Takahama, Y. Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol. 33, 256–263 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Aschenbrenner, K. et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8, 351–358 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Cowan, J.E. et al. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J. Exp. Med. 210, 675–681 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Klein, L., Kyewski, B., Allen, P.M. & Hogquist, K.A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14, 377–391 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2, 1032–1039 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Anderson, M.S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Ramsey, C. et al. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet. 11, 397–409 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Nagamine, K. et al. Positional cloning of the APECED gene. Nat. Genet. 17, 393–398 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Mathis, D. & Benoist, C. Aire. Annu. Rev. Immunol. 27, 287–312 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Peterson, P., Org, T. & Rebane, A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat. Rev. Immunol. 8, 948–957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Org, T. et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 9, 370–376 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Koh, A.S. et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc. Natl. Acad. Sci. USA 105, 15878–15883 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Org, T. et al. AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Hum. Mol. Genet. 18, 4699–4710 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Giraud, M. et al. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc. Natl. Acad. Sci. USA 109, 535–540 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Oven, I. et al. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol. Cell. Biol. 27, 8815–8823 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Abramson, J., Giraud, M., Benoist, C. & Mathis, D. Aire's partners in the molecular control of immunological tolerance. Cell 140, 123–135 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Liiv, I. et al. DNA-PK contributes to the phosphorylation of AIRE: importance in transcriptional activity. Biochim. Biophys. Acta 1783, 74–83 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Žumer, K., Low, A.K., Jiang, H., Saksela, K. & Peterlin, B.M. Unmodified histone H3K4 and DNA-dependent protein kinase recruit autoimmune regulator to target genes. Mol. Cell. Biol. 32, 1354–1362 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Waterfield, M. et al. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat. Immunol. 15, 258–265 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Herranz, D. & Serrano, M. SIRT1: recent lessons from mouse models. Nat. Rev. Cancer 10, 819–823 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Afshar, G. & Murnane, J.P. Characterization of a human gene with sequence homology to Saccharomyces cerevisiae SIR2. Gene 234, 161–168 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Gardner, J.M. et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321, 843–847 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li, H. et al. SirT1 modulates the estrogen-insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice. Breast Cancer Res. 9, R1 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gordon, J. et al. Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus. BMC Dev. Biol. 7, 69 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Feige, J.N. & Auwerx, J. Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr. Opin. Cell Biol. 20, 303–309 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang, T. & Kraus, W.L. SIRT1-dependent regulation of chromatin and transcription: linking NAD+ metabolism and signaling to the control of cellular functions. Biochim. Biophys. Acta 1804, 1666–1675 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. McBurney, M.W. et al. The mammalian SIR2α protein has a role in embryogenesis and gametogenesis. Mol. Cell. Biol. 23, 38–54 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Seifert, E.L. et al. SirT1 catalytic activity is required for male fertility and metabolic homeostasis in mice. FASEB J. 26, 555–566 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Saare, M., Rebane, A., Rajashekar, B., Vilo, J. & Peterson, P. Autoimmune regulator is acetylated by transcription coactivator CBP/p300. Exp. Cell Res. 318, 1767–1778 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Jiang, W., Anderson, M.S., Bronson, R., Mathis, D. & Benoist, C. Modifier loci condition autoimmunity provoked by Aire deficiency. J. Exp. Med. 202, 805–815 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Guerau-de-Arellano, M., Martinic, M., Benoist, C. & Mathis, D. Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity. J. Exp. Med. 206, 1245–1252 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Anderson, M.S. et al. The cellular mechanism of Aire control of T cell tolerance. Immunity 23, 227–239 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Sequeira, J. et al. sirt1-null mice develop an autoimmune-like condition. Exp. Cell Res. 314, 3069–3074 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Zhang, J. et al. The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J. Clin. Invest. 119, 3048–3058 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kong, S., McBurney, M.W. & Fang, D. Sirtuin 1 in immune regulation and autoimmunity. Immunol. Cell Biol. 90, 6–13 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Beier, U.H. et al. Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival. Mol. Cell. Biol. 31, 1022–1029 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Akimova, T. et al. Targeting sirtuin-1 alleviates experimental autoimmune colitis by induction of Foxp3+ T-regulatory cells. Mucosal Immunol. 10.1038/mi.2014.10 (2014).

  39. Sakamoto, J., Miura, T., Shimamoto, K. & Horio, Y. Predominant expression of Sir2alpha, an NAD-dependent histone deacetylase, in the embryonic mouse heart and brain. FEBS Lett. 556, 281–286 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Biason-Lauber, A. et al. Identification of a SIRT1 mutation in a family with type 1 diabetes. Cell Metab. 17, 448–455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Husebye, E.S. & Anderson, M.S. Autoimmune polyendocrine syndromes: clues to type 1 diabetes pathogenesis. Immunity 32, 479–487 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Basu, A. et al. Proteome-wide prediction of acetylation substrates. Proc. Natl. Acad. Sci. USA 106, 13785–13790 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank D. Graf (University of Zurich) for B6.Foxn1-Cre mice (with the consent of N. Manley (University of Georgia)); D. Mathis and C. Benoist (Harvard Medical School) for Aire−/− (NOD) mice; M. Anderson (University of California at San Francisco) for Aire-GFP mice; M. Oren (Weizmann Institute) for plasmid pCMV-P300; and N. Or Geva, Z. Porat, G. Hecht, Y. Peleg and O. Brenner for experimental expertise and help. Supported by the Minerva Stiftung (711423), the Israel Science Foundation (1825/10 and 722/14) and the Sy Syms Foundation (J.A.) and the Agence Nationale de Recherche (2011-CHEX-001-R12004KK to M.Gi.).

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Authors and Affiliations

  1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    Anna Chuprin, Ayelet Avin, Yael Goldfarb, Yonatan Herzig, Ben Levi, Adi Jacob, Asaf Sela, Shir Katz & Jakub Abramson

  2. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Moran Grossman & Irit Sagi

  3. Department of Immunology, Institut Cochin, INSERM U1016, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Clotilde Guyon & Matthieu Giraud

  4. The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel

    Moran Rathaus & Haim Y Cohen

  5. Ottawa Hospital Research Institute, Ottawa, Canada

    Michael W McBurney

  6. Department of Clinical Science, University of Bergen, Bergen, Norway

    Eystein S Husebye

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  1. Anna Chuprin
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Contributions

A.C. and J.A. designed the study and wrote the manuscript; A.C. performed most of the experimental work; A.A. performed experiments related to proximity ligation assays. Sirt1 deacetylation, fluorescence microscopy, analysis of serum autoantibodies by slot-blot and enzyme-linked immunosorbent assay; and Y.G., Y.H., B.L., A.J., A.S., S.K., M.Gr., C.G., M.R., H.Y.C., I.S., M.Gi., M.W.M., E.S.H. and J.A. helped in performing, analyzing and/or designing some of the experiments.

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Correspondence to Jakub Abramson.

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The authors declare no competing financial interests.

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Chuprin, A., Avin, A., Goldfarb, Y. et al. The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance. Nat Immunol 16, 737–745 (2015). https://doi.org/10.1038/ni.3194

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