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

Anna Chuprin; Ayelet Avin; Yael Goldfarb; Yonatan Herzig; Ben Levi; Adi Jacob; Asaf Sela; Shir Katz; Moran Grossman; Clotilde Guyon; Moran Rathaus; Haim Y. Cohen; Irit Sagi; Matthieu Giraud; Michael W. McBurney; Eystein S. Husebye; Jakub Abramson

doi:10.1038/ni.3194

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

Anna Chuprin, Ayelet Avin, Yael Goldfarb, Yonatan Herzig, Ben Levi, Adi Jacob, Asaf Sela, Shir Katz, Moran Grossman, Clotilde Guyon, Moran Rathaus, Haim Y. Cohen, Irit Sagi, Matthieu Giraud, Michael W. McBurney, Eystein S. Husebye, Jakub Abramson

The Mina and Everard Goodman Faculty of Life Sciences

Research output: Contribution to journal › Article › peer-review

71 Scopus citations

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.

Original language	English
Pages (from-to)	737-745
Number of pages	9
Journal	Nature Immunology
Volume	16
Issue number	7
DOIs	https://doi.org/10.1038/ni.3194
State	Published - 20 Jul 2015

Bibliographical note

Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.

Funding

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.).

Funders	Funder number
Sy Syms Foundation
Minerva Foundation	711423
Agence Nationale de la Recherche	2011-CHEX-001-R12004KK
Israel Science Foundation	722/14, 1825/10

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Chuprin, A., Avin, A., Goldfarb, Y., Herzig, Y., Levi, B., Jacob, A., Sela, A., Katz, S., Grossman, M., Guyon, C., Rathaus, M., Cohen, H. Y., Sagi, I., Giraud, M., McBurney, M. W., Husebye, E. S., & Abramson, J. (2015). The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance. Nature Immunology, 16(7), 737-745. https://doi.org/10.1038/ni.3194

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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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Chuprin, A, Avin, A, Goldfarb, Y, Herzig, Y, Levi, B, Jacob, A, Sela, A, Katz, S, Grossman, M, Guyon, C, Rathaus, M, Cohen, HY, Sagi, I, Giraud, M, McBurney, MW, Husebye, ES & Abramson, J 2015, 'The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance', Nature Immunology, vol. 16, no. 7, pp. 737-745. https://doi.org/10.1038/ni.3194

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

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