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TRAF 6 directs FOXP 3 localization and facilitates regulatory T‐cell function through K63‐linked ubiquitination
Author(s) -
Ni Xuhao,
Kou Wei,
Gu Jian,
Wei Ping,
Wu Xiao,
Peng Hao,
Tao Jinhui,
Yan Wei,
Yang Xiaoping,
Lebid Andriana,
Park Benjamin V,
Chen Zuojia,
Tian Yizhu,
Fu Juan,
Newman Stephanie,
Wang Xiaoming,
Shen Hongbin,
Li Bin,
Blazar Bruce R.,
Wang Xuehao,
Barbi Joseph,
Pan Fan,
Lu Ling
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899766
Subject(s) - biology , ubiquitin ligase , ubiquitin , transcription factor , microbiology and biotechnology , regulator , foxp3 , transcriptional regulation , regulation of gene expression , gene , genetics , immune system
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 FOXP 3. 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 FOXP 3 regulation are just beginning to be elucidated. Here, we found that TRAF 6‐deficient Tregs were dysfunctional in vivo ; mice with Treg‐restricted deletion of TRAF 6 were resistant to implanted tumors and displayed enhanced anti‐tumor immunity. We further determined that FOXP 3 undergoes K63‐linked ubiquitination at lysine 262 mediated by the E3 ligase TRAF 6. In the absence of TRAF 6 activity or upon mutation of the ubiquitination site, FOXP 3 displayed aberrant, perinuclear accumulation and disrupted regulatory function. Thus, K63‐linked ubiquitination by TRAF 6 ensures proper localization of FOXP 3 and facilitates the transcription factor's gene‐regulating activity in Tregs. These results implicate TRAF 6 as a key posttranslational, Treg‐stabilizing regulator that may be targeted in novel tolerance‐breaking therapies.