Dynamic Cellular Regulation of Proteasome Translocation and Phase Transition

Proteasome dysfunction has been implicated in the pathogenesis of many human diseases, and the proteasome system has emerged as a major therapeutic target for cancer treatment. Besides proteasome activity, the dynamics of proteasome localization provide another tier of mechanism for regulating proteasome function and cellular protein homeostasis. While proteasomes are highly enriched in the nucleus, they can dynamically reshuffle across cellular compartments in response to metabolic cues. This localization shift is coupled with autophagy as a major mechanism for cell survival under stress. Under certain metabolic stress, proteasomes can reorganize into distinct membraneless condensates, termed proteasome condensates. While the current understanding of the biological significance of proteasome condensates is limited, they may provide proteolytic control to meet metabolic needs under stress. This review highlights how distinct metabolic cues, such as carbon starvation, amino acid deficiency, and senescence, regulate divergent proteasome fates including proteasome subcellular translocation, autophagic degradation of proteasomes, and proteasome condensate formation. A better understanding of proteasome regulation in a spatiotemporal manner will help identify new therapeutic targets for diseases affected by proteasome dysfunction.