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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.
AuthorsJing Yang, Peng Xu, Lei Han, Zhixiang Guo, Xiuwen Wang, Zuojia Chen, Jia Nie, Shuying Yin, Miranda Piccioni, Andy Tsun, Ling Lv, Shenglin Ge, Bin Li
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 9 Pg. 4094-7 (May 01 2015) ISSN: 1550-6606 [Electronic] United States
PMID25821221 (Publication Type: Journal Article)
CopyrightCopyright © 2015 by The American Association of Immunologists, Inc.
Chemical References
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RNA, Messenger
  • RORC protein, human
  • USP4 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases
Topics
  • Cell Differentiation
  • Humans
  • Inflammation (genetics, immunology, metabolism, pathology)
  • Interleukin-17 (genetics, immunology)
  • Nuclear Receptor Subfamily 1, Group F, Member 3 (chemistry, genetics, metabolism)
  • RNA, Messenger (genetics)
  • Rheumatic Heart Disease (genetics, immunology, pathology)
  • Th17 Cells (immunology, metabolism)
  • Ubiquitin Thiolesterase (genetics, metabolism)
  • Ubiquitin-Specific Proteases
  • Ubiquitination

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