Publication Date:
2014-12-04
Description:
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 RORgammat, 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 RORgammat in response to TGF-beta signalling. Our data identify DUBA as a cell-intrinsic suppressor of IL-17 production.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rutz, Sascha -- Kayagaki, Nobuhiko -- Phung, Qui T -- Eidenschenk, Celine -- Noubade, Rajkumar -- Wang, Xiaoting -- Lesch, Justin -- Lu, Rongze -- Newton, Kim -- Huang, Oscar W -- Cochran, Andrea G -- Vasser, Mark -- Fauber, Benjamin P -- DeVoss, Jason -- Webster, Joshua -- Diehl, Lauri -- Modrusan, Zora -- Kirkpatrick, Donald S -- Lill, Jennie R -- Ouyang, Wenjun -- Dixit, Vishva M -- England -- Nature. 2015 Feb 19;518(7539):417-21. doi: 10.1038/nature13979. Epub 2014 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470037" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Enzyme Stability
;
Female
;
Inflammation/genetics/pathology
;
Interleukin-17/*biosynthesis
;
Intestine, Small/metabolism/pathology
;
Lymphocyte Activation
;
Mice
;
Mice, Inbred C57BL
;
Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
;
Proteasome Endopeptidase Complex/metabolism
;
Protein Binding
;
*Protein Biosynthesis
;
Signal Transduction
;
Substrate Specificity
;
Th17 Cells/*metabolism
;
Transforming Growth Factor beta/metabolism
;
Ubiquitin-Protein Ligases/metabolism
;
Ubiquitin-Specific Proteases/biosynthesis/deficiency/genetics/*metabolism
;
Ubiquitination
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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