Cutting Edge: Ubiquitin-Specific Protease 4 Promotes Th17 Cell Function under Inflammation by Deubiquitinating and Stabilizing RORγt

ROR gamma t is a key transcription factor that controls the development and function of inflammatory Th17. The mechanisms that regulate RORgt stability remain unclear. We report that Th17 cells highly express the deubiquitinase ubiquitin-specific protease (USP) 4, which is essential for maintaining RORgt 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 RORgt, thereby promoting ROR gamma t function and IL-17A transcription. Interestingly, TGF-beta plus IL-6 enhanced USP4-mediated deubiquitination of ROR gamma t. Moreover, USP4 and IL-17 mRNA, but not RORgt 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.