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

143 Scopus citations

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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  • Cite this

    Chen, Z., Barbi, J., Bu, S., Yang, H. Y., 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., ... Li, B. (2013). The ubiquitin ligase stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity, 39(2), 272-285. https://doi.org/10.1016/j.immuni.2013.08.006