Institut für Neuropathologie

DUBs negatively regulate proteolysis or other signaling functions of ubiquitination such as internalization or altered protein function by removing the ubiquitin chain from the target. The Ubiquitin isopeptidase UBPY (USP8) represents a particular interesting member of deubiquitinating enzymes as the molecule is growth regulated and contains a structural motif for SH3 domain binding. Using conditional mutagenesis we generated mice that allow the time and cell specific inactivation of UBPY in the context of the whole organism. We were able to show that lack of UBPy results in embryonic lethality, whereas its induced inactivation in adults causes fatal liver failure. The defect is accompanied by a strong reduction or absence of several growth factor receptor tyrosine kinases (RTKs) like epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-met) and ERBB3. Consequently embryonic fibroblasts undergo growth arrest upon induced deletion of UBPy. UBPy deficient cells exhibit aberrantly enlarged early endosomes colocalizing with enhanced ubiquitination and have reduced levels of HRS and STAM2. Collectively our results demonstrate that UBPy is essential for receptor tyrosine kinase stability and to maintain proper endosomal transport in vivo. Currently these mice are used to elucidate the function of UBPY specifically in the brain and diverse subsets of immune relevant cell types.