@article{2190c3e2aca7472f9b36e4e5783f7e98,
title = "Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases treg-cell-suppressive capacity",
abstract = "Stable Foxp3 expression is required for the development of functional regulatory T (Treg) cells. Here, we demonstrate that the expression of the transcription factor Foxp3 can be regulated through the polyubiquitination of multiple lysine residues, resulting in proteasome-mediated degradation. Expression of the deubiquitinase (DUB) USP7 was found to be upregulated and active in Treg cells, being associated with Foxp3 in the nucleus. Ectopic expression of USP7 decreased Foxp3 polyubiquitination and increased Foxp3 expression. Conversely, either treatment with DUB inhibitor or USP7 knockdown decreased endogenous Foxp3 protein expression and decreased Treg-cell-mediated suppression invitro. Furthermore, in a murine adoptive-transfer-induced colitis model, either inhibition of DUB activity or USP7 knockdown in Treg cells abrogated their ability to resolve inflammation invivo. Our data reveal a molecular mechanism in which rapid temporal control of Foxp3 expression in Treg cells can be regulated by USP7, thereby modulating Treg cell numbers and function.",
author = "Jorg vanLoosdregt and Veerle Fleskens and Juan Fu and Brenkman, {Arjan B.} and Bekker, {Cornelis P.J.} and Pals, {Cornelieke E.G.M.} and Jenny Meerding and Berkers, {Celia R.} and Joseph Barbi and Andrea Gr{\"o}ne and Sijts, {Alice J.A.M.} and Maurice, {Madelon M.} and Eric Kalkhoven and Prakken, {Berent J.} and Huib Ovaa and Fan Pan and Zaiss, {Dietmar M.W.} and Coffer, {Paul J.}",
note = "Funding Information: The authors like to thank M. Klein, S. Vervoort, I. Kuper, and A. Veenstra for technical assistance and S. Sakaguchi (Institute for Physical and Chemical Research, Yokohama, Japan) and B.M.T. Burgering (University Medical Center Utrecht) for providing several constructs. H.O. was supported by a VIDI grant from the Netherlands Foundation for Scientific Research. M.M.M. is supported by the Dutch Cancer Society (2006-3508), Utrecht University (High Potential Program), and the European Research Council (starting grant 242958). F.P.{\textquoteright}s research is partially supported by grants from the National Institutes of Health (R01AI099300), the Melanoma Research Alliance, a Stewart Trust Award, and a Kelly{\textquoteright}s Dream Award. J.v.L. and V.F. were supported by a grant from the Dutch Rheumatism Foundation. H.O. is a cofounder of UbiQ B.V. and a member of its scientific advisory board. ",
year = "2013",
month = aug,
day = "22",
doi = "10.1016/j.immuni.2013.05.018",
language = "English (US)",
volume = "39",
pages = "259--271",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "2",
}