The ubiquitin–proteasome pathway is a critical system for protein degradation, regulating numerous cellular processes. It involves a cascade of enzymes: E1, E2, and E3, which covalently attach ubiquitin to target proteins, marking them for degradation by the 26S proteasome or lysosomes. This system is essential for cell cycle regulation, DNA repair, immune responses, and the processing of major histocompatibility complex (MHC) class I antigens. Recent studies have shown that the pathway also targets membrane-anchored and secretory proteins, highlighting its broad cellular functions. The ubiquitin system is highly specific, with E3 enzymes recognizing substrates through primary or secondary signals, often requiring post-translational modifications or interactions with ancillary proteins. The system's specificity is determined by the interaction between E3s and their substrates, with some E3s recognizing multiple substrates via similar motifs. The degradation of proteins is tightly regulated, with certain proteins being degraded at specific times or in response to stimuli. The ubiquitin system is involved in various diseases, including cancer, neurodegenerative disorders, and genetic conditions. For example, mutations in p53 and β-catenin are linked to cancer progression, while defects in the ubiquitin system contribute to neurodegenerative diseases like Alzheimer's and Huntington's. The system also plays a role in immune responses, with viruses exploiting it to evade immune detection. The proteasome, a key component of the ubiquitin–proteasome pathway, consists of a 20S core and 19S regulatory complex. It degrades ubiquitinated proteins, and its dysfunction can lead to disease. The 26S proteasome is involved in the degradation of cell cycle regulators, while the 20S proteasome is responsible for the breakdown of proteins into peptides. The ubiquitin system also includes de-ubiquitinating enzymes that regulate the process by removing ubiquitin from proteins. Ubiquitin-like proteins, such as SUMO-1 and NEDD8, play roles in protein modification and regulation, influencing processes like DNA repair and cell signaling. These proteins are involved in various cellular functions, including the stabilization of proteins and the regulation of cell cycle progression. In summary, the ubiquitin–proteasome pathway is a fundamental mechanism for protein degradation and regulation, with wide-ranging implications for cellular function and disease. Understanding its mechanisms is crucial for developing therapeutic strategies for various diseases.The ubiquitin–proteasome pathway is a critical system for protein degradation, regulating numerous cellular processes. It involves a cascade of enzymes: E1, E2, and E3, which covalently attach ubiquitin to target proteins, marking them for degradation by the 26S proteasome or lysosomes. This system is essential for cell cycle regulation, DNA repair, immune responses, and the processing of major histocompatibility complex (MHC) class I antigens. Recent studies have shown that the pathway also targets membrane-anchored and secretory proteins, highlighting its broad cellular functions. The ubiquitin system is highly specific, with E3 enzymes recognizing substrates through primary or secondary signals, often requiring post-translational modifications or interactions with ancillary proteins. The system's specificity is determined by the interaction between E3s and their substrates, with some E3s recognizing multiple substrates via similar motifs. The degradation of proteins is tightly regulated, with certain proteins being degraded at specific times or in response to stimuli. The ubiquitin system is involved in various diseases, including cancer, neurodegenerative disorders, and genetic conditions. For example, mutations in p53 and β-catenin are linked to cancer progression, while defects in the ubiquitin system contribute to neurodegenerative diseases like Alzheimer's and Huntington's. The system also plays a role in immune responses, with viruses exploiting it to evade immune detection. The proteasome, a key component of the ubiquitin–proteasome pathway, consists of a 20S core and 19S regulatory complex. It degrades ubiquitinated proteins, and its dysfunction can lead to disease. The 26S proteasome is involved in the degradation of cell cycle regulators, while the 20S proteasome is responsible for the breakdown of proteins into peptides. The ubiquitin system also includes de-ubiquitinating enzymes that regulate the process by removing ubiquitin from proteins. Ubiquitin-like proteins, such as SUMO-1 and NEDD8, play roles in protein modification and regulation, influencing processes like DNA repair and cell signaling. These proteins are involved in various cellular functions, including the stabilization of proteins and the regulation of cell cycle progression. In summary, the ubiquitin–proteasome pathway is a fundamental mechanism for protein degradation and regulation, with wide-ranging implications for cellular function and disease. Understanding its mechanisms is crucial for developing therapeutic strategies for various diseases.