The proteasome is a large, multi-subunit protein complex found in the cytoplasm and nucleus of eukaryotic cells. Its primary function is to degrade misfolded or damaged proteins, which helps maintain cellular homeostasis and prevent the accumulation of potentially toxic protein aggregates. The proteasome identifies and degrades these proteins through a highly regulated process involving several steps:1. Recognition of target proteins: The proteasome recognizes misfolded or damaged proteins through specific degradation signals called degrons. These degrons can be specific amino acid sequences, post-translational modifications such as ubiquitination , or structural features that are exposed in misfolded proteins.2. Ubiquitination: The most common signal for proteasomal degradation is the covalent attachment of multiple ubiquitin molecules to the target protein. This process, called ubiquitination, is carried out by a cascade of enzymes, including ubiquitin-activating enzymes E1 , ubiquitin-conjugating enzymes E2 , and ubiquitin ligases E3 . The E3 ligase is responsible for substrate specificity, recognizing the degron on the target protein and transferring ubiquitin from the E2 enzyme to the target protein. The formation of a polyubiquitin chain on the target protein serves as a signal for proteasomal degradation.3. Proteasome recruitment: The 26S proteasome, which is responsible for degrading ubiquitinated proteins, consists of a 20S core particle and one or two 19S regulatory particles. The 19S regulatory particle recognizes the polyubiquitin chain on the target protein and binds to it, recruiting the substrate to the proteasome.4. Deubiquitination and unfolding: Before the target protein can be degraded, the ubiquitin chains must be removed by deubiquitinating enzymes DUBs associated with the 19S regulatory particle. Additionally, the target protein must be unfolded to fit into the narrow chamber of the 20S core particle. ATP-dependent unfoldases in the 19S regulatory particle use the energy from ATP hydrolysis to unfold the target protein and translocate it into the 20S core particle.5. Proteolysis: The 20S core particle contains multiple protease active sites that cleave the target protein into small peptides, typically 3-25 amino acids long. These peptides are then released from the proteasome and can be further degraded by cellular peptidases or recycled for amino acid reuse.6. Recycling of ubiquitin: The removed ubiquitin molecules can be recycled by the cell for further rounds of ubiquitination and protein degradation.Through this highly regulated process, the proteasome ensures that misfolded or damaged proteins are efficiently recognized, ubiquitinated, and degraded, thereby maintaining cellular protein homeostasis and preventing the accumulation of potentially harmful protein aggregates.