期刊
EMBO JOURNAL
卷 38, 期 9, 页码 -出版社
WILEY
DOI: 10.15252/embj.201899766
关键词
cancer; FOXP3; TRAF6; Tregs; ubiquitin
资金
- National Natural Science Fund of China [81571564, 91442117, 81521004, 81522020]
- 863 Young Scientists Special Fund [SS2015AA020932]
- National Science Foundation of Jiangsu Province [BK20131024, BE2016766]
- Bloomberg-Kimmel Institute
- Melanoma Research Alliance
- National Institutes of Health [R01AI099300, R01AI089830, R01AI137046, R01CA218270]
- Department of Defense [PC130767]
- Emerson Collective Award
- Johns Hopkins Discovery Award
- Roswell Park Alliance Foundation
- NCI [P30CA016056]
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 invivo; 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.
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