ubiquitinproteasomen

The ubiquitin-proteasome system (UPS) is the major ATP-dependent pathway for regulated protein degradation in eukaryotic cells. It maintains cellular proteostasis by removing misfolded or damaged proteins and by regulating the abundance of many short-lived regulatory proteins that control processes such as cell cycle progression, signaling, and transcription.

Substrate tagging begins with ubiquitination, a cascade of enzymes that includes E1 activating enzymes, E2 conjugating enzymes, and E3 ligases that confer substrate specificity. Ubiquitin can be attached as a single unit or built into polyubiquitin chains. The linkage type of these chains often encodes the substrate’s fate; for example, K48-linked chains commonly signal degradation by the proteasome, whereas other linkages can regulate signaling, localization, or trafficking.

The 26S proteasome degrades polyubiquitinated substrates. It consists of a 20S core particle with proteolytic active sites and one or more 19S regulatory particles. The 19S gate the entrance, recognize ubiquitin chains, unfold substrates in an ATP-dependent manner, and translocate them into the 20S core for proteolysis into short peptides and amino acids. Deubiquitinating enzymes (DUBs) can remove or remodel ubiquitin chains, regulating degradation timing and substrate fate.

Physiological relevance and disease associations are broad. The UPS influences cell cycle control, DNA repair, immune function, and stress responses. Dysregulation is linked to cancer, neurodegenerative diseases, and inflammatory disorders. Pharmacological inhibition of the proteasome is a therapeutic strategy in certain cancers, with agents such as bortezomib and carfilzomib illustrating clinical utility.