Modification by ubiquitination governs the half-lives of thousands of proteins that are fated for elimination by either the proteasome or autophagy pathways, depending on the intricate architectures of ubiquitin modification. This system mediates quality control for individual proteins, protein complexes, and organelles, as well as myriad purely regulatory functions. Here we provide a comprehensive survey of the ubiquitin-proteasome system (UPS), the scope of which is at present poorly defined. The UPS, with the inclusion of pathways involving ubiquitin-like modifiers, comprises in our estimate over 1430 distinct components in humans, a vast set of activities whose collective impact on the biology of the cell is pervasive. The UPS is an integral component of the proteostasis network (PN), the remainder of which is surveyed in the accompanying reports. With the addition of molecular chaperones, proteins from autophagy-lysosome pathway, and related activities, the PN includes in total over 3150 components by our estimates. Comprehensive and systematic definition of these pathways should facilitate a range of ongoing investigations in the areas of genomics, proteomics, biochemistry, cell biology, and disease research.Abbreviations: APC, anaphase promoting complex; CDD, Conserved Domain Database; CRL, cullin RING ligase; DSB, double-strand break; DUB, deubiquitinating enzyme; ERAD, ER-associated degradation; PN, proteostasis network; RBR, RING-between-RING; RCR, RING-Cys-Relay; SPOC, Structure Prediction and Omics-informed Classifier; UB, ubiquitin; UBL, ubiquitin-like; UBLM, ubiquitin-like modifier; UEV, ubiquitin-conjugating enzyme variant; UPS, ubiquitin-proteasome system.
