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 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.
authors: Department of Immunology, University Medical Center Utrecht, Utrecht 3584EA, The Netherlands.
authors: Jorg
authors: J
authors: van Loosdregt
authors: Veerle
authors: V
authors: Fleskens
authors: Juan
authors: J
authors: Fu
authors: Arjan B
authors: AB
authors: Brenkman
authors: Cornelis P J
authors: CP
authors: Bekker
authors: Cornelieke E G M
authors: CE
authors: Pals
authors: Jenny
authors: J
authors: Meerding
authors: Celia R
authors: CR
authors: Berkers
authors: Joseph
authors: J
authors: Barbi
authors: Andrea
authors: A
authors: Gröne
authors: Alice J A M
authors: AJ
authors: Sijts
authors: Madelon M
authors: MM
authors: Maurice
authors: Eric
authors: E
authors: Kalkhoven
authors: Berent J
authors: BJ
authors: Prakken
authors: Huib
authors: H
authors: Ovaa
authors: Fan
authors: F
authors: Pan
authors: Dietmar M W
authors: DM
authors: Zaiss
authors: Paul J
authors: PJ
authors: Coffer
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D003092:Colitis / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D034622:RNA Interference; D034741:RNA, Small Interfering; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D017874:Immediate-Early Proteins; D034741:RNA, Small Interfering; C499308:Rag2 protein, mouse; C064658:RAG-1 protein; C099271:Dub1 protein, mouse; D010450:Endopeptidases; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
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