The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, CD8-Positive T-Lymphocytes, Cell Differentiation, Colitis, Endopeptidases, Endosomal Sorting Complexes Required for Transport, Forkhead Transcription Factors, Homeostasis, Humans, Jurkat Cells, Mice, Receptors, Antigen, T-Cell, Receptors, Interleukin-7, T-Lymphocytes, Thymocytes, Ubiquitin Thiolesterase
Adaptor Proteins, Signal Transducing, Animals, CD8-Positive T-Lymphocytes, Cell Differentiation, Colitis, Endopeptidases, Endosomal Sorting Complexes Required for Transport, Forkhead Transcription Factors, Homeostasis, Humans, Jurkat Cells, Mice, Receptors, Antigen, T-Cell, Receptors, Interleukin-7, T-Lymphocytes, Thymocytes, Ubiquitin Thiolesterase
Nat. Immunol.
Date: Sep. 01, 2015
PubMed ID: 26214742
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