Mono- and polyubiquitination controls a multitude of cellular processes beside proteasomal degradation, including the activity of signaling cascades, DNA replication and repair, subcellular localization of proteins and virus budding. The reversibility of ubiquitination is ensured by a large group of deubiquitinating enzymes with important regulatory functions. The ubiquitin specific peptidase UBPY has a vital and non-redundant role, demonstrated by the fact that the conventional knockout of

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... is embryonically lethal. Further studies revealed a function of UBPY in endocytic trafficking and in ligand-induced downmodulation of receptor tyrosine kinases. Both mechanisms play a central role in T cell development and function. UBPY was also reported to interact with a major player in TCR signaling, the adaptor molecule GADS, and with a central regulator of T cell anergy, the E3 ligase GRAIL. To investigate the T cell specific functions of UBPY, cre/LoxP targeting was used to generate a knockout mouse model lacking UBPY exclusively in T cells (UBPY-/-T ). UBPY-/-T mice have defects in immune homeostasis, causing hyperactivation of the peripheral T cells, the spontaneous development of inflammatory bowel disease and premature death of the animals. This phenotype probably underlies a defective thymocyte development in UBPY-/-T mice leading to reduced levels of single positive thymocytes and of mature T cells. UBPY, however, is not necessary for normal proliferation of thymocytes and not for endosomal trafficking of the TCR. Rather, UBPY depletion alters TCR signal transduction, leading to stronger but more transient ERK phosphorylation after TCR stimulation. This work could thus determine a previously undescribed function of a deubiquitinating enzyme in the regulation of TCR signal kinetics, with potential importance for other signal transduction pathways.