Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity

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• 作者：Jorg van?Loosdregt ; Veerle Fleskens ; Juan Fu ; Arjan?B. Brenkman ; Cornelis?P.J. Bekker ; Cornelieke?E.G.M. Pals ; Jenny Meerding ; Celia?R. Berkers ; Joseph Barbi ; Andrea Gr?ne ; Alice?J.A.M. Sijts ; Madelon?M. Maurice ; Eric Kalkhoven ; Berent?J. Prakken ; Huib Ovaa ; Fan Pan ; Dietmar?M.W. Zaiss ; Paul?J. Coffer
• 刊名：Immunity
• 出版年：2013
• 出版时间：22 August, 2013
• 年：2013
• 卷：39
• 期：2
• 页码：259-271
• 全文大小：2462 K

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Summary

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 in?vitro. 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 in?vivo. 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.