The ubiquitin-proteasome system UPS is a crucial cellular mechanism responsible for the selective degradation and turnover of proteins within a cell. It plays a vital role in maintaining cellular homeostasis by regulating various cellular processes, including cell cycle progression, signal transduction, protein quality control, and the response to oxidative stress. The UPS consists of two main components: ubiquitin, a small protein that acts as a molecular tag, and the proteasome, a large protein complex responsible for the degradation of ubiquitinated proteins.The UPS-mediated protein degradation process involves three main steps:1. Ubiquitination: This is the process of covalently attaching ubiquitin molecules to the target protein. It is carried out 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, and the activated ubiquitin is transferred to the E2 enzyme. The E3 ligase then recognizes the target protein and facilitates the transfer of ubiquitin from E2 to the target protein. This process can be repeated, leading to the formation of a polyubiquitin chain on the target protein.2. Recognition and delivery to the proteasome: The polyubiquitinated protein is recognized by the proteasome through specific ubiquitin receptors. The 26S proteasome, the primary proteasome involved in UPS-mediated degradation, is composed of a 20S catalytic core and two 19S regulatory particles. The 19S regulatory particles recognize the polyubiquitin chain and facilitate the unfolding and translocation of the target protein into the 20S core.3. Proteolysis: The 20S core of the proteasome contains proteolytic active sites that cleave the target protein into small peptides. The ubiquitin molecules are recycled by deubiquitinating enzymes DUBs that remove the ubiquitin chains before degradation.There are several pathways that target proteins for UPS-mediated degradation:1. Quality control: Misfolded or damaged proteins are recognized by molecular chaperones and targeted for degradation by the UPS. This process ensures that only properly folded and functional proteins are present in the cell.2. Cell cycle regulation: The UPS plays a critical role in regulating cell cycle progression by controlling the levels of key regulatory proteins, such as cyclins and cyclin-dependent kinase inhibitors. The timely degradation of these proteins ensures the proper progression of the cell cycle and prevents uncontrolled cell division.3. Signal transduction: The UPS is involved in the regulation of various signaling pathways by controlling the levels of signaling molecules, such as transcription factors and kinases. This allows for the rapid and reversible modulation of cellular responses to external stimuli.4. Endoplasmic reticulum-associated degradation ERAD : Proteins that fail to fold correctly in the endoplasmic reticulum ER are retrotranslocated to the cytosol, where they are ubiquitinated and degraded by the UPS. This process helps maintain ER homeostasis and prevents the accumulation of misfolded proteins in the ER.5. Oxidative stress response: The UPS is involved in the degradation of oxidatively damaged proteins, which can be harmful to the cell. This process helps maintain cellular redox homeostasis and protects the cell from oxidative stress-induced damage.In summary, the ubiquitin-proteasome system UPS is a vital cellular mechanism responsible for the selective degradation and turnover of proteins within a cell. It plays a crucial role in maintaining cellular homeostasis by regulating various cellular processes, including protein quality control, cell cycle progression, signal transduction, and the response to oxidative stress. The UPS-mediated protein degradation process involves ubiquitination, recognition and delivery to the proteasome, and proteolysis. Several pathways target proteins for UPS-mediated degradation, including quality control, cell cycle regulation, signal transduction, ERAD, and oxidative stress response.