NDLI: Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells.

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Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Verdin, Eric Wu, Jessica Ott, Melanie Kwon, Hye-Sook Lim, Hyung W. Schnölzer, Martina
Description	Country affiliation: United States Author Affiliation: Kwon HS ( Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.)
Abstract	The Foxp3 transcription factor is the master regulator of regulatory T cell (Treg) differentiation and function. Its activity is regulated by reversible acetylation. Using mass spectrometry of immunoprecipitated proteins, we identify three novel acetylation sites in murine Foxp3 (K31, K262, and K267) and the corresponding sites in human FOXP3 proteins. Newly raised modification-specific Abs against acetylated K31 and K267 confirm acetylation of these residues in murine Tregs. Mutant Foxp3 proteins carrying arginine substitutions at the three acetylation sites (3KR) accumulate in T cells to higher levels than wild-type Foxp3 and exert better suppressive activity in coculture experiments. Acetylation and stability of wild-type, but not mutant, Foxp3 is enhanced when cells are treated with Ex-527, an inhibitor of the NAD(+)-dependent deacetylase SIRT1. Treatment with Ex-527 promotes Foxp3 expression during induced Treg differentiation, enhances Foxp3 levels in natural Tregs, and prevents loss of Foxp3 expression in adoptively transferred Tregs in mice. Our data identify SIRT1 as a negative regulator of Treg function via deacetylation of three novel target sites in Foxp3. SIRT1 inhibitors strengthen the suppressive activity of Tregs and may be useful in enhancing Treg-based therapeutic approaches to autoimmune diseases or graft rejections.
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1100903
Journal	The Journal of Immunology
Issue Number	6
Volume Number	188
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2012-03-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Forkhead Transcription Factors Chemistry Genetics Immune Tolerance Immunology T-lymphocytes, Regulatory Acetylation Adoptive Transfer Amino Acid Sequence Animals Blotting, Western Cell Differentiation Immunoprecipitation Jurkat Cells Mass Spectrometry Mice Molecular Sequence Data Rna, Messenger Reverse Transcriptase Polymerase Chain Reaction Transfection Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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