Functional role of the ubiquitin specific protease 8 (USP8/UBPy) in T cells

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Protein modification by ubiquitin controls a wide variety of basic biological processes and is counteracted by the activity of deubiquitinating enzymes. UBPy (USP8) is one of more than 80 deubiquitinating enzymes encoded in the human genome. We were able to show that UBPy regulates the stability of receptor tyrosine kinases and is essential for proper endosomal sorting in vivo. Using cre-loxP mediated gene targeting we have generated mice with T-cell specific deletion of UBPy (ΔT-UBPy) in order to analyze the function of this ubiquitin isopeptidase in T-cells, where a pleiotropy of key signalling molecules are controlled by ubiquitin mediated mechanisms. ΔT-UBPy mice show premature death and develop a severe inflammatory bowel disease (IBD). CD4+ and CD8+ single positive T-cells in thymus, lymph node and spleen are strongly reduced and upon stimulation ΔT-UBPy thymocytes showed reduced proliferative capacity. Given results reveal an essential role of UBPy in T-cell function. Using this model system we will elucidate the molecular and cellular mechanisms mediated by USP8 to gain novel insights about the role of the ubiquitin proteasome system and ubiquitin modification in T-cell signalling. A particular focus will be the regulation, specificity and functional role of ubiquitin deconjugation, which is so far poorly understood. ΔT-UBPy mice as a novel model system for IBD might also help to better understand the molecular mechanisms underlying the human autoimmune disorders Crohns- disease and ulcerative colitis.