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J Immunol. 2015 May 1;194(9):4094-7. doi: 10.4049/jimmunol.1401451. Epub 2015 Mar 27.

Cutting edge: Ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORγt.

Author information

1
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.
2
Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; and.
3
Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai 200040, China.
4
Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai 200040, China huashanlvling@sina.com aydgsl@sina.com binli@sibs.ac.cn.
5
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.
6
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.

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.

PMID:
25821221
DOI:
10.4049/jimmunol.1401451
[Indexed for MEDLINE]
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