The Ubiquitin-Proteasome System: The Cell's Natural Destroyer.

The ubiquitin-proteasome system (UPS) serves as the principal selective protein degradation machinery in eukaryotic cells, orchestrating proteostasis and regulating nearly all fundamental physiological processes. This chapter systematically delineates the UPS, tracing its discovery and dissecting its core molecular machinery. The hierarchical three-enzyme cascade directing ubiquitin tagging is described, with particular emphasis on the structural mechanisms governing ubiquitin activation and transfer. The architectural and functional organization of the 26S proteasome, which encompasses substrate recognition, deubiquitination, unfolding, and processive degradation, is comprehensively examined. In addition, the broad regulatory functions of the UPS are highlighted in the contexts of cell cycle progression, protein quality control, immune modulation, and apoptosis, and its pathological dysregulation in cancers and neurodegenerative disorders is underscored. Finally, the therapeutic landscape is surveyed, covering clinical proteasome inhibitors, agents targeting E1 and E2 enzymes, and emerging modalities such as PROTACs and molecular glues that harness E3 ligases for targeted protein degradation.