Mechanisms of substrate processing during ER-associated protein degradation

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Item Type:	Review
Title:	Mechanisms of substrate processing during ER-associated protein degradation
Creators Name:	Christianson, J.C., Jarosch, E. and Sommer, T.
Abstract:	Maintaining proteome integrity is essential for long-term viability of all organisms and is overseen by intrinsic quality control mechanisms. The secretory pathway of eukaryotes poses a challenge for such quality assurance as proteins destined for secretion enter the endoplasmic reticulum (ER) and become spatially segregated from the cytosolic machinery responsible for disposal of aberrant (misfolded or otherwise damaged) or superfluous polypeptides. The elegant solution provided by evolution is ER-membrane-bound ubiquitylation machinery that recognizes misfolded or surplus proteins or by-products of protein biosynthesis in the ER and delivers them to 26S proteasomes for degradation. ER-associated protein degradation (ERAD) collectively describes this specialized arm of protein quality control via the ubiquitin-proteasome system. But, instead of providing a single strategy to remove defective or unwanted proteins, ERAD represents a collection of independent processes that exhibit distinct yet overlapping selectivity for a wide range of substrates. Not surprisingly, ER-membrane-embedded ubiquitin ligases (ER-E3s) act as central hubs for each of these separate ERAD disposal routes. In these processes, ER-E3s cooperate with a plethora of specialized factors, coordinating recognition, transport and ubiquitylation of undesirable secretory, membrane and cytoplasmic proteins. In this Review, we focus on substrate processing during ERAD, highlighting common threads as well as differences between the many routes via ERAD.
Keywords:	Endoplasmic Reticulum, Endoplasmic Reticulum-Associated Degradation, Proteasome Endopeptidase Complex, Protein Folding, Proteolysis, Ubiquitin-Protein Ligases, Ubiquitination, Animals
Source:	Nature Reviews Molecular Cell Biology
ISSN:	1471-0072
Publisher:	Nature Publishing Group
Volume:	24
Number:	11
Page Range:	777-796
Date:	November 2023
Additional Information:	Copyright © 2023, Springer Nature Limited
Official Publication:	https://doi.org/10.1038/s41580-023-00633-8
External Fulltext:	View full text on external repository or document server
PubMed:	View item in PubMed

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