The proteasome is a complex molecular machine that degrades proteins conjugated to ubiquitin. Substrates dock onto the proteasome's regulatory particle (RP) via ubiquitin receptors and are then translocated into the 28-subunit core particle (CP) for hydrolysis. The RP contains six ATPases that form a ring complex, driving substrate unfolding and translocation. ATP-dependent deubiquitination of substrates is crucial for efficient degradation and suppressing ubiquitin degradation. The proteasome also contains deubiquitinating enzymes that act on substrates before degradation. The RP's substrate translocation channel, mediated by the ATPases, is critical for substrate entry and unfolding. The proteasome's complex structure and function involve multiple components, including the RP, CP, and various proteins that interact with ubiquitin and proteasome subunits. The proteasome plays a vital role in various cellular processes, including cell cycle control, apoptosis, inflammation, and protein quality control. Understanding the proteasome's mechanisms and regulation is essential for comprehending its functions in human health and disease.The proteasome is a complex molecular machine that degrades proteins conjugated to ubiquitin. Substrates dock onto the proteasome's regulatory particle (RP) via ubiquitin receptors and are then translocated into the 28-subunit core particle (CP) for hydrolysis. The RP contains six ATPases that form a ring complex, driving substrate unfolding and translocation. ATP-dependent deubiquitination of substrates is crucial for efficient degradation and suppressing ubiquitin degradation. The proteasome also contains deubiquitinating enzymes that act on substrates before degradation. The RP's substrate translocation channel, mediated by the ATPases, is critical for substrate entry and unfolding. The proteasome's complex structure and function involve multiple components, including the RP, CP, and various proteins that interact with ubiquitin and proteasome subunits. The proteasome plays a vital role in various cellular processes, including cell cycle control, apoptosis, inflammation, and protein quality control. Understanding the proteasome's mechanisms and regulation is essential for comprehending its functions in human health and disease.