Among the ~100 human deubiquitinating enzymes (DUBs), only three are currently defined as proteasome-associated DUBs (pDUBs). Given the dynamic nature of proteasome composition, we searched for additional pDUBs and identified USP15 as the most abundant pDUB in erythrocyte-derived proteasome preparations. CryoEM and biochemical analyses indicate that USP15 interacts with Rpn6 and Rpn13 through distinct domains. Furthermore, USP15 induces conformational changes in the 26S proteasome and helps facilitate substrate selection for efficient proteasomal degradation.
