title: Cutting edge: Ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORγt.
abstract: RORγt is a key transcription factor that controls the development and function of inflammatory Th17. The mechanisms that regulate RORγt stability remain unclear. We report that Th17 cells highly express the deubiquitinase ubiquitin-specific protease (USP)4, which is essential for maintaining RORγt and Th17 cell function. Inhibition of the catalytic activity of USP4 with vialinin A, a compound derived from Chinese traditional medicine, dampened Th17 differentiation. USP4 interacted and deubiquitinated K48-linked polyubiquitination of RORγt, thereby promoting RORγt function and IL-17A transcription. Interestingly, TGF-β plus IL-6 enhanced USP4-mediated deubiquitination of RORγt. Moreover, USP4 and IL-17 mRNA, but not RORγt mRNA, were significantly elevated in CD4(+) T cells from patients with rheumatic heart disease. Thus, USP4 could be a novel therapeutic target for the treatment of Th17-modulated autoimmune diseases.
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; and.
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.affiliation: Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; and.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Zuojia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Nie
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Shuying
authors.initials: S
authors.lastname: Yin
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Miranda
authors.initials: M
authors.lastname: Piccioni
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Andy
authors.initials: A
authors.lastname: Tsun
authors.affiliation: Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai 200040, China huashanlvling@sina.com aydgsl@sina.com binli@sibs.ac.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Lv
authors.affiliation: Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; and huashanlvling@sina.com aydgsl@sina.com binli@sibs.ac.cn.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Ge
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China huashanlvling@sina.com aydgsl@sina.com binli@sibs.ac.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
mesh_terms: D002454:Cell Differentiation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012214:Rheumatic Heart Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; C539900:RORC protein, human; C486203:USP4 protein, human; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases