TRAF6 directs FOXP3 localization and facilitates regulatory T-cell function through K63-linked ubiquitination.
EMBO J
; 38(9)2019 05 02.
Article
em En
| MEDLINE
| ID: mdl-30886050
ABSTRACT
Regulatory T cells (Tregs) are crucial mediators of immune control. The characteristic gene expression and suppressive functions of Tregs depend considerably on the stable expression and activity of the transcription factor FOXP3. Transcriptional regulation of the Foxp3 gene has been studied in depth, but both the expression and function of this factor are also modulated at the protein level. However, the molecular players involved in posttranslational FOXP3 regulation are just beginning to be elucidated. Here, we found that TRAF6-deficient Tregs were dysfunctional in vivo; mice with Treg-restricted deletion of TRAF6 were resistant to implanted tumors and displayed enhanced anti-tumor immunity. We further determined that FOXP3 undergoes K63-linked ubiquitination at lysine 262 mediated by the E3 ligase TRAF6. In the absence of TRAF6 activity or upon mutation of the ubiquitination site, FOXP3 displayed aberrant, perinuclear accumulation and disrupted regulatory function. Thus, K63-linked ubiquitination by TRAF6 ensures proper localization of FOXP3 and facilitates the transcription factor's gene-regulating activity in Tregs. These results implicate TRAF6 as a key posttranslational, Treg-stabilizing regulator that may be targeted in novel tolerance-breaking therapies.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Melanoma Experimental
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Linfócitos T Reguladores
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Colite
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Fator 6 Associado a Receptor de TNF
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Fatores de Transcrição Forkhead
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Ubiquitinação
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Lisina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China