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Decisions Underlying the Quality Control of Proteins Via the ERAD and Post-ER Degradation Pathways
PROTEIN QUALITY CONTROL IN THE EARLY SECRETORY PATHWAY
Jeffrey L. Brodsky1
1Department of Biological Sciences and the Center for Protein Conformational Diseases, University of Pittsburgh, Pittsburgh, PA 15260 USA
To maintain protein homeostasis, eukaryotes have evolved a hierarchy of protein quality control checkpoints along the secretory pathway, including endoplasmic reticulum associated degradation (ERAD) and post-ER quality control. Although most aberrant proteins in the secretory pathway are eliminated by ERAD, some misfolded proteins can exit the ER in COPII vesicles and are instead turned over by lysosomal proteases after capture by the ESCRT machinery. Other proteins, particularly those that are aggregation-prone in the ER, can alternatively be degraded by ER-phagy. To date, it remains elusive how misfolded proteins—particularly membrane proteins—are selected for one or more of these different fates. By constructing a group of model substrates and by examining human ion channels and transporters in various model systems, we are beginning to define the requirements for the targeted selection of misfolded proteins in the secretory pathway for one disposal pathway versus another. In addition, we have been able to dissect the molecular underpinnings of why some disease-causing mutations in ion channels and transporters result in disease pathology and how the defects associated with these mutant proteins might be corrected using drugs that target distinct protein quality control pathways.