title: 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.
authors.affiliation: Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Sascha
authors.initials: S
authors.lastname: Rutz
authors.affiliation: Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.affiliation: Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Qui T
authors.initials: QT
authors.lastname: Phung
authors.affiliation: Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Eidenschenk
authors.affiliation: Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Noubade
authors.affiliation: Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Lesch
authors.affiliation: Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Rongze
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Newton
authors.affiliation: Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Huang
authors.affiliation: Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cochran
authors.affiliation: Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Vasser
authors.affiliation: Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.affiliation: Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: DeVoss
authors.affiliation: Department of Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Webster
authors.affiliation: Department of Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.affiliation: Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.affiliation: Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jennie R
authors.initials: JR
authors.lastname: Lill
authors.affiliation: Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000818:Animals; D004795:Enzyme Stability; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis*; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D015398:Signal Transduction; D013379:Substrate Specificity; D058504:Th17 Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539901:Rorc protein, mouse; D016212:Transforming Growth Factor beta; C489244:UBR5 protein, mouse; D044767:Ubiquitin-Protein Ligases; C000595694:Otud5 protein, mouse; D064570:Ubiquitin-Specific Proteases; D046988:Proteasome Endopeptidase Complex