title: The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance.
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.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Chuprin
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Avin
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Goldfarb
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Herzig
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Levi
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Jacob
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Sela
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shir
authors.initials: S
authors.lastname: Katz
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Grossman
authors.affiliation: Department of Immunology, Institut Cochin, INSERM U1016, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Guyon
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Rathaus
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Haim Y
authors.initials: HY
authors.lastname: Cohen
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Sagi
authors.affiliation: Department of Immunology, Institut Cochin, INSERM U1016, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Giraud
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Jakub
authors.initials: J
authors.lastname: Abramson
mesh_terms: D000107:Acetylation; D000818:Animals; D000941:Antigens / Q000276:immunology; D061167:Central Tolerance / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology*; D059467:Transcriptome / Q000276:immunology; D000096927:AIRE Protein
chemical_list: D000941:Antigens; D053631:Interleukin Receptor Common gamma Subunit; D056564:Sirtuin 1; D014157:Transcription Factors; D000096927:AIRE Protein; C507942:Il2rg protein, mouse; C470545:Sirt1 protein, mouse