The Ubiquitin Ligase Stub1 Negatively Modulates Regulatory T Cell Suppressive Activity by Promoting Degradation of the Transcription Factor Foxp3

被引：339

作者：

Chen, Zuojia ^{[1
]}

Barbi, Joseph ^{[2
]}

Bu, Shurui ^{[2
,3
]}

Yang, Huang-Yu ^{[2
,4
]}

Li, Zhiyuan ^{[1
]}

Gao, Yayi ^{[1
]}

Jinasena, Dilini ^{[2
]}

Fu, Juan ^{[2
]}

Lin, Fang ^{[1
]}

Chen, Chen ^{[1
]}

Zhang, Jing ^{[1
,2
]}

Yu, Ning ^{[8
]}

Li, Xiangpei ^{[8
]}

Shan, Zhao ^{[1
]}

Nie, Jia ^{[1
]}

Gao, Zhimei ^{[1
]}

Tian, Hong ^{[15
]}

Li, Yangyang ^{[1
]}

Yao, Zhengju ^{[1
]}

Zheng, Ying ^{[2
]}

Park, Benjamin V. ^{[2
]}

Pan, Ziyi ^{[2
]}

Zhang, Jing ^{[1
,2
]}

Dang, Eric ^{[2
]}

Li, Zhiguang ^{[2
]}

Wang, Honglin ^{[9
]}

Luo, Weibo ^{[10
,11
,12
,13
,14
]}

Li, Liwu ^{[15
]}

Semenza, Gregg L. ^{[10
,11
,12
,13
,14
]}

Zheng, Song-Guo ^{[5
]}

Loser, Karin ^{[6
]}

Tsun, Andy ^{[1
]}

Greene, Mark I. ^{[7
]}

Pardoll, Drew M. ^{[2
]}

Pan, Fan ^{[2
]}

Li, Bin ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Pasteur Shanghai, Unit Mol Immunol,Key Lab Mol Virol & Immunol, Shanghai 200025, Peoples R China

[2] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol,Immunol & Hematopoiesis Div, Baltimore, MD 21287 USA

[3] Fudan Univ, Affiliated Jinshan Hosp, Dept Gastroenterol, Shanghai 201508, Peoples R China

[4] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp, Dept Nephrol, Tao Yuan 333, Taiwan

[5] Penn State Univ, Coll Med, Dept Med, Div Rheumatol, Hershey, PA 17033 USA

[6] Univ Munster, Dept Dermatol, D-48149 Munster, Germany

[7] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[8] Anhui Med Univ, Affiliated Anhui Prov Hosp, Dept Rheumatol & Immunol, Hefei 230001, Peoples R China

[9] Shanghai Jiao Tong Univ, Sch Med, Inst Med Sci, Shanghai Inst Immunol, Shanghai 200025, Peoples R China

[10] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[11] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[12] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[13] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD 21205 USA

[14] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA

[15] Virginia Polytech Inst & State Univ, Dept Biol Sci, Blacksburg, VA 24061 USA

来源：

IMMUNITY | 2013年 / 39卷 / 02期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

HEAT-SHOCK PROTEINS; INTESTINAL INFLAMMATION; TGF-BETA; CHIP; EXPRESSION; INDUCE; DIFFERENTIATION; ACTIVATION; PLASTICITY; STABILITY;

D O I：

10.1016/j.immuni.2013.08.006

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-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 in vitro and in vivo 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.

引用

页码：272 / 285

页数：14

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