Proteasome substrate receptors and their therapeutic potential

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2022-11, Vol.47 (11), p.950-964
• Main Authors: Osei-Amponsa, Vasty, Walters, Kylie J.
• Format: Article
• Language: English
• Subjects: Carrier Proteins - metabolism; deubiquitinating enzymes; Deubiquitinating Enzymes - metabolism; proteasome; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors; Proteins - metabolism; Proteolysis; substrate receptors; ubiquitin; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2022.06.006

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. Inhibitors against the proteasome core particle (CP) treat hematological cancers, and new therapies that target the proteasome continue to be developed.At the proteasome, substrate receptors (Rpn1, Rpn10, and Rpn13) have their own intrinsic dynamics and bind to ubiquitin chains dynamically, aiding in substrate capture and processing.Proteasome substrate receptors are multimodular, with distinct domains for binding to substrates through ubiquitin chains and to DUBs USP14 and UCHL5 or ubiquitin E3 ligase E6AP.Inducing proteasomal degradation is done naturally by pathogens that generate neo-substrates through Rpn10 and E6AP and a PROTAC has been developed against Rpn13.