title: The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3.
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.
authors: 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.
authors: Zuojia
authors: Z
authors: Chen
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Joseph
authors: J
authors: Barbi
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Affiliated Jinshan Hospital, Fudan University, Shanghai, 201508, China.
authors: Shurui
authors: S
authors: Bu
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Nephrology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
authors: Huang-Yu
authors: HY
authors: Yang
authors: 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.
authors: Zhiyuan
authors: Z
authors: Li
authors: 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.
authors: Yayi
authors: Y
authors: Gao
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Dilini
authors: D
authors: Jinasena
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Juan
authors: J
authors: Fu
authors: 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.
authors: Fang
authors: F
authors: Lin
authors: 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.
authors: Chen
authors: C
authors: Chen
authors: 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.
authors: Jing
authors: J
authors: Zhang
authors: Department of Rheumatology & Immunology, Affiliated Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China.
authors: Ning
authors: N
authors: Yu
authors: Department of Rheumatology & Immunology, Affiliated Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China.
authors: Xiangpei
authors: X
authors: Li
authors: 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.
authors: Zhao
authors: Z
authors: Shan
authors: 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.
authors: Jia
authors: J
authors: Nie
authors: 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.
authors: Zhimei
authors: Z
authors: Gao
authors: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors: Hong
authors: H
authors: Tian
authors: 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.
authors: Yangyang
authors: Y
authors: Li
authors: 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.
authors: Zhengju
authors: Z
authors: Yao
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Ying
authors: Y
authors: Zheng
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Benjamin V
authors: BV
authors: Park
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Ziyi
authors: Z
authors: Pan
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Jing
authors: J
authors: Zhang
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Eric
authors: E
authors: Dang
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Zhiguang
authors: Z
authors: Li
authors: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors: Honglin
authors: H
authors: Wang
authors: Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Weibo
authors: W
authors: Luo
authors: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors: Liwu
authors: L
authors: Li
authors: Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Gregg L
authors: GL
authors: Semenza
authors: Department of Medicine, Autoimmunity Research Center, Penn State University College of Medicine, Hershey, PA, 17033, USA.
authors: Song-Guo
authors: SG
authors: Zheng
authors: Department of Dermatology, University of Münster, D-48149 Münster, Germany.
authors: Karin
authors: K
authors: Loser
authors: 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.
authors: Andy
authors: A
authors: Tsun
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadephia, PA 19104, USA.
authors: Mark I
authors: MI
authors: Greene
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Drew M
authors: DM
authors: Pardoll
authors: Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Fan
authors: F
authors: Pan
authors: 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.
authors: Bin
authors: B
authors: Li
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D011725:Pyridines; D034622:RNA Interference; D034741:RNA, Small Interfering; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018840:HSP70 Heat-Shock Proteins; D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D034741:RNA, Small Interfering; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; C093642:SB 203580
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