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:	Jorg van Loosdregt, Diede Brunen, Veerle Fleskens, Cornelieke E G M Pals, Eric W F Lam, Paul J Coffer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e5310b45f1a746f49c5370dcb0f464d9
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spelling	oai:doaj.org-article:e5310b45f1a746f49c5370dcb0f464d92021-11-18T06:55:26ZRapid temporal control of Foxp3 protein degradation by sirtuin-1.1932-620310.1371/journal.pone.0019047https://doaj.org/article/e5310b45f1a746f49c5370dcb0f464d92011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21533107/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Maintenance 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.Jorg van LoosdregtDiede BrunenVeerle FleskensCornelieke E G M PalsEric W F LamPaul J CofferPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e19047 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jorg van Loosdregt Diede Brunen Veerle Fleskens Cornelieke E G M Pals Eric W F Lam Paul J Coffer Rapid temporal control of Foxp3 protein degradation by sirtuin-1.
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.
format	article
author	Jorg van Loosdregt Diede Brunen Veerle Fleskens Cornelieke E G M Pals Eric W F Lam Paul J Coffer
author_facet	Jorg van Loosdregt Diede Brunen Veerle Fleskens Cornelieke E G M Pals Eric W F Lam Paul J Coffer
author_sort	Jorg van Loosdregt
title	Rapid temporal control of Foxp3 protein degradation by sirtuin-1.
title_short	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_sort	rapid temporal control of foxp3 protein degradation by sirtuin-1.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/e5310b45f1a746f49c5370dcb0f464d9
work_keys_str_mv	AT jorgvanloosdregt rapidtemporalcontroloffoxp3proteindegradationbysirtuin1 AT diedebrunen rapidtemporalcontroloffoxp3proteindegradationbysirtuin1 AT veerlefleskens rapidtemporalcontroloffoxp3proteindegradationbysirtuin1 AT corneliekeegmpals rapidtemporalcontroloffoxp3proteindegradationbysirtuin1 AT ericwflam rapidtemporalcontroloffoxp3proteindegradationbysirtuin1 AT pauljcoffer rapidtemporalcontroloffoxp3proteindegradationbysirtuin1
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Rapid temporal control of Foxp3 protein degradation by sirtuin-1.

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