TRAF6 directs FOXP3 localization and facilitates regulatory T-cell function through K63-linked ubiquitination

Xuhao Ni, Wei Kou, Jian Gu, Ping Wei, Xiao Wu, Hao Peng, Jinhui Tao, Wei Yan, Xiaoping Yang, Andriana Lebid, Benjamin V. Park, Zuojia Chen, Yizhu Tian, Juan Fu, Stephanie Newman, Xiaoming Wang, Hongbin Shen, Bin Li, Bruce R. Blazar, Xuehao WangJoseph Barbi, Fan Pan, Ling Lu

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish (US)
Article numbere99766
JournalEMBO Journal
Volume38
Issue number9
DOIs
StatePublished - May 2 2019

Bibliographical note

Funding Information:
L.L.’s research is supported by the National Natural Science Fund of China (grants 81571564, grant 91442117, grants 81521004 and 81522020), the 863 Young Scientists Special Fund (grant SS2015AA020932), National Science Foundation of Jiangsu Province BK20131024, BE2016766. We thank H. K. Lin (Wake Forest University School of Medicine, USA) for valuable reagents. F.P.’s research was supported by grants from the Bloomberg-Kimmel Institute, the Melanoma Research Alliance, the National Institutes of Health (R01AI099300, R01AI089830, R01AI137046, and R01CA218270), Department of Defense (PC130767), Emerson Collective Award, and Johns Hopkins Discovery Award. F.P. is a Stewart Trust Scholar; J.B.’s research is supported by a grant from the Roswell Park Alliance Foundation and NCI grant P30CA016056.

Funding Information:
L.L.'s research is supported by the National Natural Science Fund of China (grants 81571564, grant 91442117, grants 81521004 and 81522020), the 863 Young Scientists Special Fund (grant SS2015AA020932), National Science Foundation of Jiangsu Province BK20131024, BE2016766. We thank H. K. Lin (Wake Forest University School of Medicine, USA) for valuable reagents. F.P.'s research was supported by grants from the Bloomberg-Kimmel Institute, the Melanoma Research Alliance, the National Institutes of Health (R01AI099300, R01AI089830, R01AI137046, and R01CA218270), Department of Defense (PC130767), Emerson Collective Award, and Johns Hopkins Discovery Award. F.P. is a Stewart Trust Scholar; J.B.'s research is supported by a grant from the Roswell Park Alliance Foundation and NCI grant P30CA016056.

Publisher Copyright:
© 2019 The Authors. Published under the terms of the CC BY 4.0 license

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • FOXP3
  • TRAF6
  • Tregs
  • cancer
  • ubiquitin

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