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.
MeSH terms
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Animals
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Enzyme Stability
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Female
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Inflammation / genetics
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Inflammation / pathology
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Interleukin-17 / biosynthesis*
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Intestine, Small / metabolism
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Intestine, Small / pathology
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Lymphocyte Activation
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Mice
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Mice, Inbred C57BL
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding
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Protein Biosynthesis*
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Signal Transduction
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Substrate Specificity
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Th17 Cells / metabolism*
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Transforming Growth Factor beta / metabolism
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitin-Specific Proteases / biosynthesis
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Ubiquitin-Specific Proteases / deficiency
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Ubiquitin-Specific Proteases / genetics
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Ubiquitin-Specific Proteases / metabolism*
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Ubiquitination
Substances
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Interleukin-17
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Rorc protein, mouse
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Transforming Growth Factor beta
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UBR5 protein, mouse
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Ubiquitin-Protein Ligases
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Otud5 protein, mouse
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Ubiquitin-Specific Proteases
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Proteasome Endopeptidase Complex