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 Schonle, Annette Aichem, Thorsten Kurz, Andreas Schlosser, Deborah Yablonski, Marcus Groettrup, Thorsten Buch, Ari Waisman, Wolfgang W. Schamel, Marco Prinz, Klaus Peter Knobeloch

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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 + γ δ 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.

Original languageEnglish
Pages (from-to)950-960
Number of pages11
JournalNature Immunology
Volume16
Issue number9
DOIs
StatePublished - 19 Aug 2015

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