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.

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…5d). Ubiquitylation of FOXP3, RORγt and T-bet controls transcription factor stability, and dysregulation of the ubiquitylating or de-ubiquitylating enzymes can induce phenotypic plasticity in these cells [183][184][185] . Blocking the activity of sirtuin 1 preserves FOXP3 acetylation, enhancing FOXP3 stability and T Reg cell function 186,187 , whereas inhibition of sirtuin 1 increases RORγt acety lation in T H 17 cells, which impedes RORγt activity 188 , thus creating another therapeutically exploitable dichotomy between inflammatory and regulatory cells.…”

Ubiquitination of RORγt at Lysine 446 Limits Th17 Differentiation by Controlling Coactivator Recruitment

“…Reports have suggested a role for ubiquitination in the regulation of RORγt stability (34–37). However, in our studies, RORγt WT and the K446R mutant expressed at similar levels (Fig.3A, 3F and 3G).…”

“…Less is known about the mechanisms of post-transcriptional regulation that is responsible for regulating RORγt function. Reports that RORγt stability is regulated by ubiquitination-mediated degradation mechanisms (34–37) suggested a role for ubiquitination in RORγt-mediated differentiation. In this study, we identified RORγt K446 as a ubiquitination site that limits Th17 differentiation by interfering with the recruitment of co-activator SRC1.…”

“…One of the functions of ubiquitination is to regulate protein stability by inducing protein degradation. Evidence indicates that RORγt stability can be regulated by ubiquitination (34–37). Another important role for ubiquitination is to regulate protein-protein interactions.…”

Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function

“…First, USP4 deubiquitylates Ro52 in transformed cell lines 72 and thus limits the expression of cytokines needed for Th17 generation 69 . Second, it directly interacts with RORγT in primary human Th17 cells and deubiquitylates RORγT in transformed cell lines 73 . USP17 (also known as DUB-3) is a second DUB that maintains RORγT stability 74 .…”