title: TRAF5-mediated Lys-63-linked Polyubiquitination Plays an Essential Role in Positive Regulation of RORγt in Promoting IL-17A Expression.
abstract: Retinoid-related orphan nuclear receptor γt (RORγt) is a key transcription factor for the development and function of Th17 cells. In this study, we show that tumor necrosis factor receptor-associated factor 5 (TRAF5), known as an E3 ubiquitin protein ligase and signal transducer, interacts with and ubiquitinates RORγt via Lys-63-linked polyubiquitination. TRAF5 stabilizes the RORγt protein level depending on its RING finger domain. Depletion of TRAF5 in Th17 cells destabilizes RORγt protein and down-regulates Th17-related genes, including IL-17A, an inflammatory cytokine involved in pathogenic mechanisms of several autoimmune diseases such as systemic lupus erythematosus. Moreover, up-regulation of the TRAF5 mRNA level was found in systemic lupus erythematosus patient CD4(+) T cells. Our findings reveal a direct link between TRAF5-mediated ubiquitination and RORγt protein regulation, which may aggravate inflammatory progress and provide new therapeutic drug targets for autoimmune diseases.
authors.affiliation: From the Division of Rheumatology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Wang
authors.affiliation: the Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: From the Division of Rheumatology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: From the Division of Rheumatology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China.
authors.forename: Kaixia
authors.initials: K
authors.lastname: Zhao
authors.affiliation: the Department of Immunology, Anhui Medical University, Hefei 230032, China, and.
authors.forename: Qingsi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: the Department of Pathology and Laboratory Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756.
authors.forename: Liming
authors.initials: L
authors.lastname: Bao
authors.affiliation: the Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: From the Division of Rheumatology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China, huashanlvling@sina.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Lv
authors.affiliation: the Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, China, binli@sibs.ac.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
mesh_terms: D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D048015:TNF Receptor-Associated Factor 5 / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: C508717:IL17A protein, human; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D048015:TNF Receptor-Associated Factor 5; D008239:Lysine
keywords: RORγt; T helper cells; TNF receptor-associated factor (TRAF); autoimmune disease; transcription factor; ubiquitylation (ubiquitination)