Deubiquitinase DUBA is a post-translational brake on interleukin-17 production in T cells

Abstract

T-helper type 17 (TH17) cells that produce the cytokines interleukin-17A (IL-17A) and IL-17F are implicated in the pathogenesis of several autoimmune diseases. The differentiation of TH17 cells is regulated by transcription factors such as RORγt, but post-translational mechanisms preventing the rampant production of pro-inflammatory IL-17A have received less attention. Here we show that the deubiquitylating enzyme DUBA is a negative regulator of IL-17A production in T cells. Mice with DUBA-deficient T cells developed exacerbated inflammation in the small intestine after challenge with anti-CD3 antibodies. DUBA interacted with the ubiquitin ligase UBR5, which suppressed DUBA abundance in naive T cells. DUBA accumulated in activated T cells and stabilized UBR5, which then ubiquitylated RORγt in response to TGF-β signalling. Our data identify DUBA as a cell-intrinsic suppressor of IL-17 production.

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

“…Despite the reduced numbers of T H cells in the LP of Hic1 DT mice and the dysregulated production of IL-17A by HIC1-deficient T H 17 cells, we failed to observe any significant differences in intestinal architecture between naive Hic1 fl/fl or Hic1 DT mice (Figure 6a, left panels). After induction of intestinal inflammation with intraperitoneal injection of a monoclonal antibody against CD3, [30][31][32] Hic1 DT mice displayed less intestinal inflammation compared with control Hic1 fl/fl mice (Figures 6a and b). Although we observed fewer CD4 þ T cells in the intestine of treated Hic1 DT mice (Figure 6c), we did observe an increase in the number of CD4 þ T cells in the LP of treated Hic1 DT mice compared with naive Hic1 DT mice (Figures 2a and b), further demonstrating that intestinal migration is not completely impaired in the absence of HIC1.…”

DUBA-UBR5 axis: other than transactivation

“…The paper by Rutz et al [4] highlighted a similar regulation in RORγt protein degradation, which is mediated by DUBA and UBR5. The finding of ubiquitylation of RORγt has expanded our understanding of the dynamic nature of RORγt protein in the stabilization of Th17 cell subset at the posttranslational level.…”

“…Although a number of groups have reported the detailed transcriptomic analysis of Th17 cells, the protein-protein network that governs the development of Th17 cells has not been established. Rutz et al [4] now report a novel deubiquitlylating enzyme DUBA, which plays a critical role in IL-17 production.…”

“…Another protein USP17 was shown as a deubiquitinase for RORγt, which stabilizes RORγt expression and promotes the function of Th17 cells [5]. Rutz et al [4] identified the enzyme which mediates opposite function in that it induces reversible covalent modification of RORγt. UBR5 was demonstrated to promote RORγt ubiquitylation and target it for proteosomal degradation.…”

“…In the paper by Rutz et al [4], the coupling between the deubiquitinase DUBA and the ubiquitin ligase UBR5 serves another purpose. The associa-npg tion of DUBA stabilizes UBR5 and reciprocally, UBR5 destabilizes DUBA through ubiquitylation.…”