Protein degradation is a central process that maintains cellular protein quality and adjusts protein levels in response to changing conditions. Cells use several highly regulated systems to recognize, modify and dismantle proteins, thereby controlling signaling, metabolism and cell survival.

The ubiquitin proteasome system is a major pathway. Proteins destined for destruction are tagged with ubiquitin by a cascade of enzymes, then delivered to the proteasome, a large protease complex that unfolds and degrades them into short peptides. Specificity is encoded by E3 ligases that recognize particular substrates, often in response to phosphorylation or other post translational modifications. This system regulates cell cycle progression, transcription factors and misfolded proteins.

Autophagy is another key route. Portions of cytoplasm, including protein aggregates and even entire organelles, are sequestered into double membrane vesicles called autophagosomes that fuse with lysosomes for bulk degradation. Selective autophagy receptors guide particular cargos, linking ubiquitin signals to the autophagic machinery.

Misfolded or damaged proteins in the endoplasmic reticulum are handled by ER associated degradation. They are recognized, retrotranslocated to the cytosol, ubiquitinated and degraded by the proteasome, helping prevent toxic accumulation.

Recent research dissects how degradation is targeted with such precision, using structural biology to reveal proteasome and ligase mechanisms, and proteomics to map ubiquitination sites on a proteome wide scale. These insights are driving new therapeutics, including drugs that inhibit the proteasome and molecular degraders that force disease causing proteins into the cell’s existing breakdown pathways.