Protein degradation is a tightly regulated process that controls protein quality, abundance and function in cells. Most intracellular proteins are degraded by the ubiquitin proteasome system. In this pathway, target proteins are tagged with chains of the small protein ubiquitin through the coordinated action of E1 activating enzymes, E2 conjugating enzymes and E3 ligases, which confer substrate specificity. Polyubiquitinated proteins are then recognized and broken down into short peptides by the 26S proteasome, a large ATP dependent protease complex. This system removes misfolded or damaged proteins and dynamically adjusts levels of regulators such as transcription factors and cell cycle proteins.

Selective degradation occurs in response to specific signals. For example, controlled ubiquitination of key signaling molecules shapes pathways that govern immunity, development and stress responses. Recent work has uncovered detailed structural and mechanistic insights into how particular E3 ligases recognize their substrates and how different types of ubiquitin chains encode distinct functional outcomes.

Protein degradation can also be exploited therapeutically. Small molecules known as molecular glues or proteolysis targeting chimeras (PROTACs) recruit disease related proteins to E3 ligases, forcing their ubiquitination and destruction. This strategy can eliminate targets that are difficult to inhibit with conventional drugs, including transcription factors and scaffolding proteins. Early clinical studies are testing degraders against cancers and inflammatory diseases, while newer designs aim to improve selectivity, oral bioavailability and control over degradation timing.

Together, these advances highlight protein degradation as both a central homeostatic mechanism and a powerful basis for next generation medicines.