Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity.
Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity.
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去泛素酶USP7对转录因子FOXP3的稳定增加了Treg-Cell抑制能力。
DOI：
10.1016/j.immuni.2013.05.018
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发表时间：
2013-08-22
期刊：
影响因子：
32.4
通讯作者：
Coffer PJ
中科院分区：
文献类型：
--
作者：
van Loosdregt J;Fleskens V;Fu J;Brenkman AB;Bekker CP;Pals CE;Meerding J;Berkers CR;Barbi J;Gröne A;Sijts AJ;Maurice MM;Kalkhoven E;Prakken BJ;Ovaa H;Pan F;Zaiss DM;Coffer PJ
Foxp3的稳定表达是功能调节性T （Treg）细胞发育所必需的。在这里，我们证明转录因子Foxp3的表达可以通过多个赖氨酸残基的多泛素化来调节，从而导致蛋白酶体介导的降解。去泛素酶（DUB） USP7在Treg细胞中表达上调并活跃，与细胞核中的Foxp3相关。USP7异位表达降低Foxp3多泛素化，增加Foxp3表达。相反，DUB抑制剂或USP7敲低均可降低内源性Foxp3蛋白表达，并降低treg细胞介导的体外抑制。此外，在小鼠过继性转移诱导的结肠炎模型中，抑制Treg细胞DUB活性或敲低USP7都会破坏它们在体内解决炎症的能力。我们的数据揭示了一种分子机制，即USP7可以调节Treg细胞中Foxp3表达的快速时间控制，从而调节Treg细胞的数量和功能。
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.
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