Developing a ubiquitin-dependent proteasome activity reporter to screen for activators and inhibitors

The 26S proteasome mediates both ubiquitin-dependent and ubiquitin-independent protein degradation and plays critical roles in the immune response, stress response and gene regulation. Current proteasome inhibitors, targeting only the rather nonspecific core particle, have nevertheless shown efficacy in cancer but they indiscriminately affect most functions of the proteasomes. With the help of Q-FASTR grant, we have successfully invented a novel and powerful screening platform for testing inhibitors that distinguish between ubiquitin-dependent and independent activities. We have performed initial screening and identified novel inhibitors with such specificity. By precisely modulating selected activities of the proteasome, these new classes of inhibitors could advance the treatment of cancer, inflammation and neurodegenerative disease. Currently, we are looking for partners to bring the project to the next phase.