Abstract
The 26S proteasome is a 2.5-MDa protease complex responsible for the selective and ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Proteasome-mediated protein degradation accounts for ~70% of all cellular proteolysis under basal conditions, and thereby any dysfunction can lead to drastic changes in cell homeostasis. A major function of ubiquitylation is to target proteins for proteasomal degradation. Accompanied by deciphering the structural diversity of ubiquitin chains with eight linkages and chain lengths, the ubiquitin code for proteasomal degradation has been expanding beyond the best-characterized Lys48-linked ubiquitin chains. Whereas polyubiquitylated proteins can be directly recognized by the proteasome, in several cases, these proteins need to be extracted or segregated by the conserved ATPases associated with diverse cellular activities (AAA)-family ATPase p97/valosin-containing protein (VCP) complex and escorted to the proteasome by ubiquitin-like (UBL)–ubiquitin associated (UBA) proteins; these are called substrate-shuttling factors. Furthermore, proteasomes are highly mobile and are appropriately spatiotemporally regulated in response to different cellular environments and stresses. In this review, we highlight an emerging key link between p97, shuttling factors, and proteasome for efficient proteasomal degradation. We also present evidence that proteasome-containing nuclear foci form by liquid–liquid phase separation under acute hyperosmotic stress.
Highlights
The ubiquitin–proteasome system is the primary degradation system in eukaryotic cells
We describe the recent progress in our research on factors upstream of the proteasome, including substrate shuttling factors and p97, the selectivity of the ubiquitin chain for proteasomal degradation, and recently identified nuclear proteasome droplets that are formed under the hyperosmotic stress triggered by multivalent interactions between RAD23B and ubiquitylated proteins to be degraded
In a p97 temperature-sensitive mutant, ubiquitylated substrates showed significant accumulation on the proteasome. This accumulation was almost completely abolished by the knockout of rad23 and dsk2, suggesting that Rad23 and Dsk2 are downstream factors of p97, reminiscent of the escort model originally described by Richly et al [34]. These findings indicated that the p97–Rad23/Dsk2 axis plays a major role in ubiquitin-dependent proteasomal degradation rather than in direct proteasomal recognition and degradation
Summary
The ubiquitin–proteasome system is the primary degradation system in eukaryotic cells. We describe the recent progress in our research on factors upstream of the proteasome, including substrate shuttling factors and p97, the selectivity of the ubiquitin chain for proteasomal degradation, and recently identified nuclear proteasome droplets that are formed under the hyperosmotic stress triggered by multivalent interactions between RAD23B and ubiquitylated proteins to be degraded. These findings underline the multi-step regulation of proteasome responding to the cellular environment
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