Regulation via compartmentation: adaptive localization of the proteasome under stress.

Protein degradation by the ubiquitin-proteasome system and autophagy are essential mechanisms that are involved in virtually all cellular activities, and their inadequate function was shown to underlie the pathogenesis of various medical conditions. Much of the study into these proteolytic systems has been focused on the components that facilitate the selective substrate identification and targeting for degradation. Given that most of the specific breakdown of proteins is mediated via their modification by ubiquitin, much research was dedicated to the enzymes which are responsible for substrate recognition and ubiquitination-E3 ubiquitin ligases. In addition to the complexity of substrate recognition and targeting for degradation, the mechanisms governing proteasome function were found to be tightly regulated, including the assembly of the different proteasomal sub-complexes, its different compositions and specialized subtypes such as the immunoproteasome, posttranslational modification of proteasomal subunits, and adaptations in its activity in face of different cellular states and stress conditions. Studies from recent years have highlighted an as-yet unexplored tier of proteasome regulation, namely its subcellular compartmentation and trafficking. Intracellular proteasome shuttling was shown to serve as an essential stress-coping mechanism in tumor cells and is emerging as a potential target for therapeutic interventions.