The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3

Immunity. 2013 Aug 22;39(2):272-85. doi: 10.1016/j.immuni.2013.08.006.

Zuojia Chen ^# ¹, Joseph Barbi ^# ², Shurui Bu ^# ² ³, Huang-Yu Yang ² ⁴, Zhiyuan Li ¹, Yayi Gao ¹, Dilini Jinasena ², Juan Fu ², Fang Lin ¹, Chen Chen ¹, Jing Zhang ¹, Ning Yu ⁵, Xiangpei Li ⁵, Zhao Shan ¹, Jia Nie ¹, Zhimei Gao ¹, Hong Tian ⁶, Yangyang Li ¹, Zhengju Yao ¹, Ying Zheng ², Benjamin V Park ², Ziyi Pan ², Jing Zhang ², Eric Dang ², Zhiguang Li ², Honglin Wang ⁷, Weibo Luo ⁸, Liwu Li ⁶, Gregg L Semenza ⁸, Song-Guo Zheng ⁹, Karin Loser ¹⁰, Andy Tsun ¹, Mark I Greene ¹¹, Drew M Pardoll ², Fan Pan ², Bin Li ¹

Affiliations

1 Key Laboratory of Molecular Virology & Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, China.
2 Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3 Affiliated Jinshan Hospital, Fudan University, Shanghai, 201508, China.
4 Department of Nephrology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
5 Department of Rheumatology & Immunology, Affiliated Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China.
6 Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
7 Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
8 Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
9 Department of Medicine, Autoimmunity Research Center, Penn State University College of Medicine, Hershey, PA, 17033, USA.
10 Department of Dermatology, University of Münster, D-48149 Münster, Germany.
11 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadephia, PA 19104, USA.
# Contributed equally.

PMID: 23973223 DOI: 10.1016/j.immuni.2013.08.006

Abstract

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.

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