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Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation

Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
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Pharmaceuticals 2020, 13(6), 128; https://doi.org/10.3390/ph13060128
Received: 8 June 2020 / Revised: 19 June 2020 / Accepted: 22 June 2020 / Published: 23 June 2020
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)
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. View Full-Text
Keywords: proteasome; protein degradation; ubiquitin; proteasomal ubiquitin receptors; p97/VCP; liquid–liquid phase separation proteasome; protein degradation; ubiquitin; proteasomal ubiquitin receptors; p97/VCP; liquid–liquid phase separation
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Tsuchiya, H.; Endo, A.; Saeki, Y. Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation. Pharmaceuticals 2020, 13, 128.

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