The covalent attachment of ubiquitin to substrate proteins by the Ubiquitin-Proteasome System (UPS) controls the stability, interactions, activity and/or localization of the proteome. The UPS governs most if not all cellular processes, including protein homeostasis (proteostasis), signal transduction, stress responses, DNA repair and replication, chromosome segregation, gene expression, vesicle trafficking and autophagy. UPS misregulation is implicated in many human diseases including cancer, neurodegeneration, metabolic disorders, infection and immunity. The covalent attachment of ubiquitin to substrates is mediated by an E1-E2-E3 enzyme cascade that activates ubiquitin as a thioester linkage and then conjugates ubiquitin to protein lysine residues as an isopeptide bond. Over 1000 known and predicted E3 enzymes recognize a vast constellation of sequence elements in substrates termed degrons. Ubiquitin conjugation is dynamic as it can be reversed by a plethora of deubiquitinating enzymes (DUBs). Different E2 and E3 enzymes generate distinct types of ubiquitin chains that direct substrates for destruction by the 26S proteasome and other fates, as readout by a host of ubiquitin binding domain proteins (UBPs). The intricate ubiquitin code governed by these writers, erasers, and readers is underpinned by a complex manifold of substrate-enzyme interactions that still remain largely uncharted. The complexity of the ubiquitin code derives from the facts that E3s usually have multiple substrates, many substrates are targeted by more than one E3, and degrons can be degenerate and/or combinatorial in nature. Indeed, the majority of UPS substrates directly identified by mass spectrometry have not been linked to an E3 enzyme. To facilitate understanding of the UPS and its links to disease, the UPS curation project aims to comprehensively curate the biomedical literature for the protein and genetic interactions of all UPS genes/proteins in humans, budding yeast and other model species. In addition, the UPS project curates sites of protein ubiquitination and chemical modulators of UPS enzymes. The UPS project is based on curated lists of 299 yeast and 1,283 human genes that are either known or inferred to function in the UPS network. The project will be expanded to include other ubiquitin-like modifiers (ULMs) as separate themed projects including for SUMO, ATG8/ATG12, URM1, UFM1, FAT10, and ISG15.

The Ubiquitin-Proteasome System curation project is on-going and will be updated each month. If you notice errors or missing interactions/publications in this dataset, or otherwise wish to contribute to this project, please contact us at support@thebiogrid.org. All Ubiquitin database records are freely available for download from links within this project.