ubiquitinproteasome

The ubiquitin-proteasome system (UPS) is the major pathway for regulated protein degradation in eukaryotic cells. It controls protein levels, quality control, and various signaling processes, and also contributes to antigen processing for immune surveillance. The UPS operates by marking proteins for destruction and then degrading them in the proteasome.

Ubiquitination is carried out by three classes of enzymes. E1 ubiquitin-activating enzymes activate ubiquitin in an ATP-dependent manner, E2 ubiquitin-conjugating enzymes carry the activated ubiquitin, and E3 ubiquitin ligases confer substrate specificity by transferring ubiquitin to lysine residues on target proteins. Proteins can be tagged with a single ubiquitin or with polyubiquitin chains; Lys48-linked chains commonly signal for degradation, while other linkages participate in signaling, localization, or non-proteolytic roles.

The core of the degradative machinery is the 26S proteasome, composed of a 20S core particle and one or two 19S regulatory particles. The 19S cap recognizes ubiquitinated substrates, removes some ubiquitin chains, unfolds the substrate, and gates its entry into the 20S core. The 20S proteolytic core then degrades the unfolded protein into short peptides. The process is ATP-dependent and involves coordinated regulation by deubiquitinating enzymes that edit ubiquitin signals during substrate processing.

The UPS influences many cellular processes, including cell cycle control, DNA repair, transcription, and stress responses. It also plays a key role in quality control by removing damaged or misfolded proteins and generating peptides for major histocompatibility complex class I antigen presentation. Dysfunctions in the UPS are linked to cancer, neurodegenerative diseases, and inflammatory conditions. Proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, are used clinically in cancer therapy, illustrating the system’s therapeutic relevance.