The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells

Almut Dufner; Agnes Kisser; Sandra Niendorf; Anja Basters; Sonja Reissig; Anne Schönle; Annette Aichem; Thorsten Kurz; Andreas Schlosser; Deborah Yablonski; Marcus Groettrup; Thorsten Buch; Ari Waisman; Wolfgang W Schamel; Marco Prinz; Klaus-Peter Knobeloch

doi:10.1038/ni.3230

The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells

Nat Immunol. 2015 Sep;16(9):950-60. doi: 10.1038/ni.3230. Epub 2015 Jul 27.

Authors

Almut Dufner¹, Agnes Kisser², Sandra Niendorf², Anja Basters¹, Sonja Reissig³, Anne Schönle¹, Annette Aichem⁴, Thorsten Kurz⁵, Andreas Schlosser⁵, Deborah Yablonski⁶, Marcus Groettrup⁷, Thorsten Buch⁸, Ari Waisman³, Wolfgang W Schamel⁹, Marco Prinz¹⁰, Klaus-Peter Knobeloch¹¹

Affiliations

¹ Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
² Leibniz Institute for Molecular Pharmacology, Berlin, Germany.
³ Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
⁴ Biotechnology Institute Thurgau at the University of Konstanz, Kreuzlingen, Switzerland.
⁵ Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany.
⁶ Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
⁷ 1] Biotechnology Institute Thurgau at the University of Konstanz, Kreuzlingen, Switzerland. [2] Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.
⁸ 1] Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universität München, Germany. [2] Institute of Laboratory Animal Sciences, University of Zurich, Zurich, Switzerland.
⁹ 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.
¹⁰ 1] Institute of Neuropathology, University of Freiburg, Freiburg, Germany. [2] BIOSS Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
¹¹ 1] Institute of Neuropathology, University of Freiburg, Freiburg, Germany. [2] Leibniz Institute for Molecular Pharmacology, Berlin, Germany.

PMID: 26214742
DOI: 10.1038/ni.3230

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.

Publication types

Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Adaptor Proteins, Signal Transducing / immunology
Adaptor Proteins, Signal Transducing / metabolism
Animals
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
Cell Differentiation / genetics
Cell Differentiation / immunology*
Colitis / genetics
Colitis / immunology
Endopeptidases / genetics
Endopeptidases / immunology*
Endosomal Sorting Complexes Required for Transport / genetics
Endosomal Sorting Complexes Required for Transport / immunology*
Forkhead Box Protein O1
Forkhead Transcription Factors / immunology
Forkhead Transcription Factors / metabolism
Homeostasis
Humans
Jurkat Cells
Mice
Receptors, Antigen, T-Cell / immunology
Receptors, Antigen, T-Cell / metabolism
Receptors, Interleukin-7 / immunology
Receptors, Interleukin-7 / metabolism
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
Thymocytes / immunology*
Thymocytes / metabolism
Ubiquitin Thiolesterase / genetics
Ubiquitin Thiolesterase / immunology*

Substances

Adaptor Proteins, Signal Transducing
Endosomal Sorting Complexes Required for Transport
FOXO1 protein, human
Forkhead Box Protein O1
Forkhead Transcription Factors
Foxo1 protein, mouse
GRAP2 protein, human
Mona protein, mouse
Receptors, Antigen, T-Cell
Receptors, Interleukin-7
Endopeptidases
USP8 protein, human
Ubiquitin Thiolesterase
Usp8 protein, mouse