The ubiquitin ligase stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3

Zuojia Chen, Joseph Barbi, Shurui Bu, Huang Yu Yang, Zhiyuan Li, Yayi Gao, Dilini Jinasena, Juan Fu, Fang Lin, Chen Chen, Jing Zhang, Ning Yu, Xiangpei Li, Zhao Shan, Jia Nie, Zhimei Gao, Hong Tian, Yangyang Li, Zhengju Yao, Ying ZhengBenjamin V. Park, Ziyi Pan, Jing Zhang, Eric Dang, Zhiguang Li, Honglin Wang, Weibo Luo, Liwu Li, Gregg L. Semenza, Song Guo Zheng, Karin Loser, Andy Tsun, Mark I. Greene, Drew M. Pardoll, Fan Pan, Bin Li

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive Tcells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector Tcell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharides lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses invitro and invivo and conferred a T-helper-1-cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection, and cancer.

Original languageEnglish (US)
Pages (from-to)272-285
Number of pages14
JournalImmunity
Volume39
Issue number2
DOIs
StatePublished - Aug 22 2013

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Regulatory T-Lymphocytes
Ligases
Ubiquitin
Transcription Factors
Th1 Cells
Ubiquitin-Protein Ligases
Autoimmunity
Autoimmune Diseases
Lipopolysaccharides
Down-Regulation
Cytokines
Inflammation
Phenotype
Infection
Neoplasms

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

The ubiquitin ligase stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. / Chen, Zuojia; Barbi, Joseph; Bu, Shurui; Yang, Huang Yu; Li, Zhiyuan; Gao, Yayi; Jinasena, Dilini; Fu, Juan; Lin, Fang; Chen, Chen; Zhang, Jing; Yu, Ning; Li, Xiangpei; Shan, Zhao; Nie, Jia; Gao, Zhimei; Tian, Hong; Li, Yangyang; Yao, Zhengju; Zheng, Ying; Park, Benjamin V.; Pan, Ziyi; Zhang, Jing; Dang, Eric; Li, Zhiguang; Wang, Honglin; Luo, Weibo; Li, Liwu; Semenza, Gregg L.; Zheng, Song Guo; Loser, Karin; Tsun, Andy; Greene, Mark I.; Pardoll, Drew M.; Pan, Fan; Li, Bin.

In: Immunity, Vol. 39, No. 2, 22.08.2013, p. 272-285.

Research output: Contribution to journalArticle

Chen, Z, Barbi, J, Bu, S, Yang, HY, Li, Z, Gao, Y, Jinasena, D, Fu, J, Lin, F, Chen, C, Zhang, J, Yu, N, Li, X, Shan, Z, Nie, J, Gao, Z, Tian, H, Li, Y, Yao, Z, Zheng, Y, Park, BV, Pan, Z, Zhang, J, Dang, E, Li, Z, Wang, H, Luo, W, Li, L, Semenza, GL, Zheng, SG, Loser, K, Tsun, A, Greene, MI, Pardoll, DM, Pan, F & Li, B 2013, 'The ubiquitin ligase stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3', Immunity, vol. 39, no. 2, pp. 272-285. https://doi.org/10.1016/j.immuni.2013.08.006
Chen, Zuojia ; Barbi, Joseph ; Bu, Shurui ; Yang, Huang Yu ; Li, Zhiyuan ; Gao, Yayi ; Jinasena, Dilini ; Fu, Juan ; Lin, Fang ; Chen, Chen ; Zhang, Jing ; Yu, Ning ; Li, Xiangpei ; Shan, Zhao ; Nie, Jia ; Gao, Zhimei ; Tian, Hong ; Li, Yangyang ; Yao, Zhengju ; Zheng, Ying ; Park, Benjamin V. ; Pan, Ziyi ; Zhang, Jing ; Dang, Eric ; Li, Zhiguang ; Wang, Honglin ; Luo, Weibo ; Li, Liwu ; Semenza, Gregg L. ; Zheng, Song Guo ; Loser, Karin ; Tsun, Andy ; Greene, Mark I. ; Pardoll, Drew M. ; Pan, Fan ; Li, Bin. / The ubiquitin ligase stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. In: Immunity. 2013 ; Vol. 39, No. 2. pp. 272-285.
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abstract = "Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive Tcells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector Tcell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharides lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses invitro and invivo and conferred a T-helper-1-cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection, and cancer.",
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AU - Chen, Zuojia

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AU - Bu, Shurui

AU - Yang, Huang Yu

AU - Li, Zhiyuan

AU - Gao, Yayi

AU - Jinasena, Dilini

AU - Fu, Juan

AU - Lin, Fang

AU - Chen, Chen

AU - Zhang, Jing

AU - Yu, Ning

AU - Li, Xiangpei

AU - Shan, Zhao

AU - Nie, Jia

AU - Gao, Zhimei

AU - Tian, Hong

AU - Li, Yangyang

AU - Yao, Zhengju

AU - Zheng, Ying

AU - Park, Benjamin V.

AU - Pan, Ziyi

AU - Zhang, Jing

AU - Dang, Eric

AU - Li, Zhiguang

AU - Wang, Honglin

AU - Luo, Weibo

AU - Li, Liwu

AU - Semenza, Gregg L.

AU - Zheng, Song Guo

AU - Loser, Karin

AU - Tsun, Andy

AU - Greene, Mark I.

AU - Pardoll, Drew M.

AU - Pan, Fan

AU - Li, Bin

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