title: Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1.
abstract: Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells' signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; Clinical Immunology Center, Third Affiliated Hospital at Sun Yat-Sen University, Guangzhou, 510630, China;
authors.forename: Yayi
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033; Institute for Immunity and Transplantation, Shanghai East Hospital, Tongji University, Shanghai, 200120, China;
authors.forename: Jiayou
authors.initials: J
authors.lastname: Tang
authors.affiliation: Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033;
authors.forename: Weiqian
authors.initials: W
authors.lastname: Chen
authors.affiliation: Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China;
authors.forename: Jia
authors.initials: J
authors.lastname: Nie
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China;
authors.forename: Fang
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Immunology, Anhui Medical University, Hefei, 230032, China;
authors.forename: Qingsi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China;
authors.forename: Zuojia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China;
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Institute for Immunity and Transplantation, Shanghai East Hospital, Tongji University, Shanghai, 200120, China;
authors.forename: Huimin
authors.initials: H
authors.lastname: Fan
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China;
authors.forename: Andy
authors.initials: A
authors.lastname: Tsun
authors.affiliation: Department of Immunology, Anhui Medical University, Hefei, 230032, China;
authors.forename: Jijia
authors.initials: J
authors.lastname: Shen
authors.affiliation: Clinical Immunology Center, Third Affiliated Hospital at Sun Yat-Sen University, Guangzhou, 510630, China;
authors.forename: Guihua
authors.initials: G
authors.lastname: Chen
authors.affiliation: Institute for Immunity and Transplantation, Shanghai East Hospital, Tongji University, Shanghai, 200120, China;
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN 55905.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
authors.affiliation: Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033;
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Olsen
authors.affiliation: Clinical Immunology Center, Third Affiliated Hospital at Sun Yat-Sen University, Guangzhou, 510630, China; Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033; szheng1@hmc.psu.edu binli@sibs.ac.cn.
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; szheng1@hmc.psu.edu binli@sibs.ac.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C000595916:KIAA1967 protein, mouse
keywords: Deleted in breast cancer 1; FOXP3 complex; inflammation; regulatory T cells