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

Bar-Ilan University - Azrieli Faculty of Medicine

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

73 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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