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

被引：264

作者：

van Loosdregt, Jorg ^{[1
,2
,3
]}

Fleskens, Veerle ^{[1
,3
]}

Fu, Juan ^{[5
]}

Brenkman, Arjan B. ^{[4
]}

Bekker, Cornelis P. J. ^{[3
,6
]}

Pals, Cornelieke E. G. M. ^{[1
,3
]}

Meerding, Jenny ^{[2
]}

Berkers, Celia R. ^{[8
]}

Barbi, Joseph ^{[5
]}

Grone, Andrea ^{[7
]}

Sijts, Alice J. A. M. ^{[6
]}

Maurice, Madelon M. ^{[3
]}

Kalkhoven, Eric ^{[4
]}

Prakken, Berent J. ^{[2
]}

Ovaa, Huib ^{[7
]}

Pan, Fan ^{[5
]}

Zaiss, Dietmar M. W. ^{[6
]}

Coffer, Paul J. ^{[1
,2
,3
]}

机构：

[1] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Immunol, NL-3584 EA Utrecht, Netherlands

[2] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Ctr Mol & Cellular Intervent, NL-3584 EA Utrecht, Netherlands

[3] Univ Med Ctr Utrecht, Dept Cell Biol, NL-3584 EA Utrecht, Netherlands

[4] Univ Med Ctr Utrecht, NL-3584 EA Utrecht, Netherlands

[5] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Immunol & Hematopoiesis Div, Baltimore, MD 21231 USA

[6] Fac Vet Med Utrecht, Dept Immunol & Infect Dis, NL-3584 CL Utrecht, Netherlands

[7] Fac Vet Med Utrecht, Dept Pathobiol, NL-3584 CL Utrecht, Netherlands

[8] Netherlands Canc Inst, Div Cell Biol, NL-1066 CX Amsterdam, Netherlands

来源：

IMMUNITY | 2013年 / 39卷 / 02期

基金：

美国国家卫生研究院; 欧洲研究理事会;

关键词：

REGULATORY T-CELLS; MEDIATED DEGRADATION; EXPRESSION; UBIQUITINATION; PLASTICITY; DISEASE; MONOUBIQUITINATION; DIFFERENTIATION; CONTRIBUTES; METHYLATION;

D O I：

10.1016/j.immuni.2013.05.018

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：259 / 271

页数：13

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