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


Dufner, Almut; Kisser, Agnes; Niendorf, Sandra; Basters, Anja; Reissig, Sonja; Schönle, Anne; Aichem, Annette; Kurz, Thorsten; Schlosser, Andreas; Yablonski, Deborah; Groettrup, Marcus; Buch, Thorsten; Waisman, Ari; Schamel, Wolfgang W; Prinz, Marco; Knobeloch, Klaus-Peter (2015). The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells. Nature Immunology, 16(9):950-960.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Laboratory Animal Science
Dewey Decimal Classification:570 Life sciences; biology
590 Animals (Zoology)
610 Medicine & health
Date:2015
Deposited On:24 Feb 2016 17:26
Last Modified:05 Apr 2016 20:10
Publisher:Nature Publishing Group
ISSN:1529-2908
Publisher DOI:https://doi.org/10.1038/ni.3230
PubMed ID:26214742

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