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 Wang & 3 others Joseph Barbi, Fan Pan, Ling Lu

Research output: Contribution to journalArticle

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

Fingerprint

TNF Receptor-Associated Factor 6
T-cells
Ubiquitination
Regulatory T-Lymphocytes
Tumors
Transcription Factors
Genes
Ubiquitin-Protein Ligases
Gene expression
Lysine
Immunity
Neoplasms
Gene Expression
Mutation

Keywords

  • cancer
  • FOXP3
  • TRAF6
  • Tregs
  • ubiquitin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

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

In: EMBO Journal, Vol. 38, No. 9, e99766, 02.05.2019.

Research output: Contribution to journalArticle

Ni, X, Kou, W, Gu, J, Wei, P, Wu, X, Peng, H, Tao, J, Yan, W, Yang, X, Lebid, A, Park, BV, Chen, Z, Tian, Y, Fu, J, Newman, S, Wang, X, Shen, H, Li, B, Blazar, BR, Wang, X, Barbi, J, Pan, F & Lu, L 2019, 'TRAF6 directs FOXP3 localization and facilitates regulatory T-cell function through K63-linked ubiquitination', EMBO Journal, vol. 38, no. 9, e99766. https://doi.org/10.15252/embj.201899766
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. / TRAF6 directs FOXP3 localization and facilitates regulatory T-cell function through K63-linked ubiquitination. In: EMBO Journal. 2019 ; Vol. 38, No. 9.
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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.",
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AU - Wei, Ping

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AU - Peng, Hao

AU - Tao, Jinhui

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AU - Yang, Xiaoping

AU - Lebid, Andriana

AU - Park, Benjamin V.

AU - Chen, Zuojia

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AU - Fu, Juan

AU - Newman, Stephanie

AU - Wang, Xiaoming

AU - Shen, Hongbin

AU - Li, Bin

AU - Blazar, Bruce R.

AU - Wang, Xuehao

AU - Barbi, Joseph

AU - Pan, Fan

AU - Lu, Ling

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