UbiquitinProteasomSystem

The ubiquitin-proteasome system (UPS) is a major pathway for selective protein degradation in eukaryotic cells. Proteins targeted for destruction are covalently tagged with ubiquitin, a 76-amino-acid protein. The tagging involves a cascade of enzymatic steps: E1 activating enzyme uses ATP to activate ubiquitin; E2 conjugating enzyme transfers ubiquitin; E3 ligase confers substrate specificity and attaches ubiquitin to lysine residues, generating mono-ubiquitination or polyubiquitin chains. Polyubiquitin chains linked through Lys48 typically signal degradation by the 26S proteasome, while other linkages regulate localization, activity, or signaling.

The 26S proteasome is a protease complex comprising a 20S core particle and 19S regulatory particles that recognize ubiquitinated substrates, unfold them, and translocate them into the 20S core for proteolysis into short peptides. The system is tightly regulated by deubiquitinases that edit and recycle ubiquitin. UPS maintains protein homeostasis, controls cell cycle progression, DNA repair, antigen presentation, and signaling pathways.

Dysregulation is implicated in diseases including neurodegenerative disorders, cancers, and inflammatory diseases. Therapeutic approaches include proteasome inhibitors (e.g., bortezomib) for multiple myeloma and other malignancies, as well as strategies targeting E3 ligases or employing targeted protein degradation technologies (PROTACs). The UPS also intersects with cellular stress responses and aging.