Recent Insights into Mechanisms Regulating the Proteasome: Implications for Human Disease

Since its discovery several decades ago, the proteasome has been recognized as one of the most complex and highly evolved proteolytic systems. Through the selective and rapid degradation of ubiquitinated proteins, it plays a pivotal role in maintaining cellular proteostasis and governing essential biological processes such as cell cycle regulation and signal transduction. Recent advances in cryo-electron microscopy (cryo-EM), together with developments in mass spectrometry and large-scale genetic screening, have provided unprecedented insights into proteasome biology. These approaches have not only revealed the proteasome as a precisely engineered molecular machine optimized for substrate specificity and efficient degradation, but have also facilitated the identification of previously unrecognized regulatory factors and post-translational modifications that fine-tune its activity. Moreover, accumulating evidence has demonstrated that proteasome capacity is tightly regulated at multiple levels, including transcriptional control, assembly dynamics, and subcellular localization, to meet diverse cellular demands and preserve proteostasis. Importantly, dysregulation of these processes is linked to human diseases, underscoring the proteasome's central role in cellular physiology and its promise as a therapeutic target. Ongoing research is uncovering new regulatory layers and structural complexities, highlighting the proteasome's indispensable and versatile role in health and disease.