In all cells, regulated proteolysis constantly sculpt and reshape the proteome. It is essential for regulation of cellular activities, for elimination of misfolded proteins and for amino acid recycling under starvation conditions. At the same time, proteolysis is a deleterious process that can prove deadly to the cell. Accordingly, mechanisms have evolved that allow intracellular proteolysis to occur in a carefully regulated manner. For instance, AAA+ proteases, enzymes that catalyze most regulated proteolysis in the cell, are well designed to carefully chose and degrade their substrates while avoiding uncontrolled degradation of other cellular proteins. In eukaryotes, the 26S proteasome is the only AAA+ protease acting in the cytoplasm and nucleus, where it degrades predominantly ubiquitin-tagged proteins. In analogy, the bacterial proteasome relies on a prokaryotic ubiquitin-like protein (Pup) for protein tagging.
The Pup-proteasome system (PPS) is much simpler than its eukaryotic counterpart. Consequently, it is highly attractive for comprehensive studies of the mechanisms underlying the activity and regulation of a multicomponent protein tagging and degradation system. While much exciting information has accumulated in recent years regarding the mechanism of action, regulation and physiological roles of the PPS, many intriguing questions remain unanswered. For instance, it is still poorly understood how protein substrates are selected for tagging by PafA, how the PPS senses starvation and how its activity is controlled in response to external stimuli. Work in our lab addresses such questions in a quest to understand the molecular design of a complex proteolytic pathway. To learn more, check out our research directions.
