Proteasome substrate receptors and their therapeutic potential

The ubiquitin-proteasome system (UPS) is critical for protein quality control and regulating protein lifespans. Following ubiquitination, UPS substrates bind multidomain receptors that, in addition to ubiquitin-binding sites, contain functional domains that bind to deubiquitinating enzymes (DUBs) or the E3 ligase E6AP/UBE3A. We provide an overview of the proteasome, focusing on its receptors and DUBs. We highlight the key role of dynamics and importance of the substrate receptors having domains for both binding and processing ubiquitin chains. The UPS is rich with therapeutic opportunities, with proteasome inhibitors used clinically and ongoing development of small molecule proteolysis targeting chimeras (PROTACs) for the degradation of disease-associated proteins. We discuss the therapeutic potential of proteasome receptors, including hRpn13, for which PROTACs have been developed.