The Ubiquitin-Proteasome System UPS is a highly regulated and selective cellular machinery responsible for the degradation of specific proteins. This process is crucial for maintaining cellular homeostasis, controlling protein quality, and regulating various cellular processes such as cell cycle progression, signal transduction, and immune responses. The UPS involves two main components: ubiquitin, a small protein modifier, and the proteasome, a large multi-subunit protease complex.The selective targeting and degradation of specific proteins by the UPS involve several steps:1. Ubiquitination: The process begins with the covalent attachment of ubiquitin molecules to the target protein. This is facilitated by a cascade of three enzymes: ubiquitin-activating enzyme E1 , ubiquitin-conjugating enzyme E2 , and ubiquitin ligase E3 . The E1 enzyme activates ubiquitin in an ATP-dependent manner, forming a high-energy thioester bond between the C-terminus of ubiquitin and the active site cysteine of E1. The activated ubiquitin is then transferred to the active site cysteine of the E2 enzyme. Finally, the E3 ligase recognizes the target protein and facilitates the transfer of ubiquitin from E2 to a lysine residue on the target protein, forming an isopeptide bond. This process is repeated, resulting in the formation of a polyubiquitin chain on the target protein.2. Recognition by the proteasome: The 26S proteasome, the primary protease complex responsible for degrading ubiquitinated proteins, recognizes the polyubiquitin chain on the target protein. The 26S proteasome is composed of a 20S catalytic core and two 19S regulatory particles. The 19S regulatory particles recognize and bind to the polyubiquitin chain, allowing the target protein to be unfolded and translocated into the 20S core.3. Degradation by the proteasome: The 20S core of the proteasome contains proteolytic active sites that cleave the target protein into small peptides. This process is highly regulated and requires ATP hydrolysis for unfolding and translocation of the target protein. The resulting peptides are then released from the proteasome and further degraded by cellular peptidases into amino acids, which can be reused for protein synthesis.4. Recycling of ubiquitin: During the degradation process, the polyubiquitin chain is disassembled by deubiquitinating enzymes DUBs , which cleave the isopeptide bonds between ubiquitin molecules. This allows ubiquitin to be recycled and reused for subsequent rounds of protein ubiquitination and degradation.In summary, the Ubiquitin-Proteasome System selectively targets specific proteins for degradation through a series of coordinated enzymatic reactions involving ubiquitination, recognition by the proteasome, proteolysis, and recycling of ubiquitin. This process is essential for maintaining cellular homeostasis and regulating various cellular processes.