Ubiquitin-proteasome system

The ubiquitin-proteasome system (UPS) is a major route for selective degradation of short-lived, misfolded, or regulatory proteins, complementary to autophagy-lysosomal degradation. Target proteins are tagged with ubiquitin chains via E1 activating, E2 conjugating, and E3 ligase enzymes, with the E3 ligase providing substrate specificity; K48-linked polyubiquitin chains are the canonical proteasome-targeting signal, while other linkages have non-degradative roles. Tagged proteins are then unfolded and degraded into short peptides inside the 26S proteasome. UPS activity declines with age, contributing to loss of proteostasis and neurodegeneration.