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Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1

Maintenance of Foxp3 protein expression in regulatory T cells (Treg) is crucial for a balanced immune response. We have previously demonstrated that Foxp3 protein stability can be regulated through acetylation, however the specific mechanisms underlying this observation remain unclear. Here we demon...

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Autores principales: van Loosdregt, Jorg, Brunen, Diede, Fleskens, Veerle, Pals, Cornelieke E. G. M., Lam, Eric W. F., Coffer, Paul J.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080399/
https://www.ncbi.nlm.nih.gov/pubmed/21533107
http://dx.doi.org/10.1371/journal.pone.0019047
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author van Loosdregt, Jorg
Brunen, Diede
Fleskens, Veerle
Pals, Cornelieke E. G. M.
Lam, Eric W. F.
Coffer, Paul J.
author_facet van Loosdregt, Jorg
Brunen, Diede
Fleskens, Veerle
Pals, Cornelieke E. G. M.
Lam, Eric W. F.
Coffer, Paul J.
author_sort van Loosdregt, Jorg
collection PubMed
description Maintenance of Foxp3 protein expression in regulatory T cells (Treg) is crucial for a balanced immune response. We have previously demonstrated that Foxp3 protein stability can be regulated through acetylation, however the specific mechanisms underlying this observation remain unclear. Here we demonstrate that SIRT1 a member of the lysine deacetylase Sirtuin (SIRT) family, but not the related SIRTs 2–7, co-localize with Foxp3 in the nucleus. Ectopic expression of SIRT1, but not SIRTs 2–7 results in decreased Foxp3 acetylation, while conversely inhibition of endogenous SIRT activity increased Foxp3 acetylation. We show that SIRT1 inhibition decreases Foxp3 poly-ubiquitination, thereby increasing Foxp3 protein levels. Co-transfection of SIRT1 with Foxp3 results in increased Foxp3 proteasomal degradation, while SIRT inhibition increases FOXP3 transcriptional activity in human Treg. Taken together, these data support a central role for SIRT1 in the regulation of Foxp3 protein levels and thereby in regulation of Treg suppressive capacity. Pharmacological modulation of SIRT1 activity in Treg may therefore provide a novel therapeutic strategy for controlling immune responses.
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spelling pubmed-30803992011-04-29 Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1 van Loosdregt, Jorg Brunen, Diede Fleskens, Veerle Pals, Cornelieke E. G. M. Lam, Eric W. F. Coffer, Paul J. PLoS One Research Article Maintenance of Foxp3 protein expression in regulatory T cells (Treg) is crucial for a balanced immune response. We have previously demonstrated that Foxp3 protein stability can be regulated through acetylation, however the specific mechanisms underlying this observation remain unclear. Here we demonstrate that SIRT1 a member of the lysine deacetylase Sirtuin (SIRT) family, but not the related SIRTs 2–7, co-localize with Foxp3 in the nucleus. Ectopic expression of SIRT1, but not SIRTs 2–7 results in decreased Foxp3 acetylation, while conversely inhibition of endogenous SIRT activity increased Foxp3 acetylation. We show that SIRT1 inhibition decreases Foxp3 poly-ubiquitination, thereby increasing Foxp3 protein levels. Co-transfection of SIRT1 with Foxp3 results in increased Foxp3 proteasomal degradation, while SIRT inhibition increases FOXP3 transcriptional activity in human Treg. Taken together, these data support a central role for SIRT1 in the regulation of Foxp3 protein levels and thereby in regulation of Treg suppressive capacity. Pharmacological modulation of SIRT1 activity in Treg may therefore provide a novel therapeutic strategy for controlling immune responses. Public Library of Science 2011-04-20 /pmc/articles/PMC3080399/ /pubmed/21533107 http://dx.doi.org/10.1371/journal.pone.0019047 Text en van Loosdregt et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
van Loosdregt, Jorg
Brunen, Diede
Fleskens, Veerle
Pals, Cornelieke E. G. M.
Lam, Eric W. F.
Coffer, Paul J.
Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1
title Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1
title_full Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1
title_fullStr Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1
title_full_unstemmed Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1
title_short Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1
title_sort rapid temporal control of foxp3 protein degradation by sirtuin-1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080399/
https://www.ncbi.nlm.nih.gov/pubmed/21533107
http://dx.doi.org/10.1371/journal.pone.0019047
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