title: The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells.
abstract: The modification of proteins by ubiquitin has a major role in cells of the immune system and is counteracted by various deubiquitinating enzymes (DUBs) with poorly defined functions. Here we identified the ubiquitin-specific protease USP8 as a regulatory component of the T cell antigen receptor (TCR) signalosome that interacted with the adaptor Gads and the regulatory molecule 14-3-3β. Caspase-dependent processing of USP8 occurred after stimulation of the TCR. T cell-specific deletion of USP8 in mice revealed that USP8 was essential for thymocyte maturation and upregulation of the gene encoding the cytokine receptor IL-7Rα mediated by the transcription factor Foxo1. Mice with T cell-specific USP8 deficiency developed colitis that was promoted by disturbed T cell homeostasis, a predominance of CD8(+) γδ T cells in the intestine and impaired regulatory T cell function. Collectively, our data reveal an unexpected role for USP8 as an immunomodulatory DUB in T cells.
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Dufner
authors.affiliation: Leibniz Institute for Molecular Pharmacology, Berlin, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Kisser
authors.affiliation: Leibniz Institute for Molecular Pharmacology, Berlin, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Niendorf
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Basters
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Reissig
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schönle
authors.affiliation: Biotechnology Institute Thurgau at the University of Konstanz, Kreuzlingen, Switzerland.
authors.forename: Annette
authors.initials: A
authors.lastname: Aichem
authors.affiliation: Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kurz
authors.affiliation: Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlosser
authors.affiliation: Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Deborah
authors.initials: D
authors.lastname: Yablonski
authors.affiliation: 1] Biotechnology Institute Thurgau at the University of Konstanz, Kreuzlingen, Switzerland. [2] Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Groettrup
authors.affiliation: 1] Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universität München, Germany. [2] Institute of Laboratory Animal Sciences, University of Zurich, Zurich, Switzerland.
authors.forename: Thorsten
authors.identifier: 0000000222369074
authors.initials: T
authors.lastname: Buch
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Ari
authors.identifier: 0000000343048234
authors.initials: A
authors.lastname: Waisman
authors.affiliation: 1] Department of Molecular Immunology, Faculty of Biology, and Center of Chronic Immunodeficiency, University of Freiburg, Freiburg, Germany. [2] BIOSS Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Schamel
authors.affiliation: 1] Institute of Neuropathology, University of Freiburg, Freiburg, Germany. [2] BIOSS Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: 1] Institute of Neuropathology, University of Freiburg, Freiburg, Germany. [2] Leibniz Institute for Molecular Pharmacology, Berlin, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000235:genetics / Q000276:immunology; D010450:Endopeptidases / Q000235:genetics / Q000276:immunology*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000276:immunology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056827:Endosomal Sorting Complexes Required for Transport; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C409587:GRAP2 protein, human; C498726:Mona protein, mouse; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; C541536:Usp8 protein, mouse