Abstract
The diverse functions of proteins depend on their proper three-dimensional folding and assembly. Misfolded cellular proteins can potentially harm cells by forming aggregates in their resident compartments that can interfere with vital cellular processes or sequester important factors. Protein quality control (PQC) pathways are responsible for the repair or destruction of these abnormal proteins. Most commonly, the ubiquitin-proteasome system (UPS) is employed to recognize and degrade those proteins that cannot be refolded by molecular chaperones. Misfolded substrates are ubiquitylated by a subset of ubiquitin ligases (also called E3s) that operate in different cellular compartments. Recent research in Saccharomyces cerevisiae has shown that the most prominent ligases mediating cytoplasmic and nuclear PQC have overlapping yet distinct substrate specificities. Many substrates have been characterized that can be targeted by more than one ubiquitin ligase depending on their localization, and cytoplasmic PQC substrates can be directed to the nucleus for ubiquitylation and degradation. Here, we review some of the major yeast PQC ubiquitin ligases operating in the nucleus and cytoplasm, as well as current evidence indicating how these ligases can often function redundantly toward substrates in these compartments.
Highlights
This review will focus on the model eukaryote Saccharomyces cerevisiae, where many of the fundamental discoveries about ER-associated degradation (ERAD) and other protein quality control (PQC) degradation pathways have been made, and detail how the primary PQC ubiquitin ligases operate within the nucleus and cytoplasm and how they overlap in their compartment-specific substrate recognition properties
When misfolded proteins cannot be refolded by molecular chaperones, they are degraded by the ubiquitin-proteasome system or selective autophagy
Chaperone proteins carry out various functions to mediate transport and degradation of cytoplasmic proteins in the nucleus and may have slightly different functions when working with different E3 enzymes
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Misfolded proteins can be found in all compartments of the cell, and diverse pathways to handle these proteins are necessary in each. When abnormal proteins cannot be refolded, their destruction is accomplished in large part by the actions of the ubiquitin-proteasome system (UPS) [2]. Such aberrant proteins often form intracellular aggregates that can be toxic to cells if they are not cleared in a timely fashion. PQC is, vital to cell health, but the exact mechanisms by which misfolded proteins are recognized and directed to the diverse pathways of the UPS remain to be resolved
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