The degradation of misfolded proteins in the ER

Abstract

To maintain protein homeostasis (i.e., “proteostasis”) and withstand the toxic effects brought about by the presence of misfolded proteins, eukaryotes have evolved a hierarchy of quality control checkpoints along the secretory pathway. The most prominent quality control step in this pathway, which acts during or soon after proteins are synthesized, is endoplasmic reticulum associated degradation (ERAD). The importance of this pathway is underscored by the fact that ~80 different protein substrates of the ERAD pathway have been linked to human disease. Although most misfolded proteins in the secretory pathway are eliminated by ERAD, others can exit the ER in COPII vesicles and are instead turned over by lysosomal proteases. This post‐ER quality control event requires the ESCRT machinery. A different class of secreted proteins, particularly those that are aggregation‐prone, can alternatively be degraded by ER‐phagy. To date, it remains elusive how these diverse misfolded proteins‐‐which can trigger various stress responses‐‐are selected for different fates. However, by constructing a collection of model substrates and examining wild‐type and disease‐associated mutant forms of various proteins, we are beginning to define the requirements for the targeted selection of misfolded proteins in the secretory pathway for one fate versus another. This pursuit represents a vital step toward the development of pharmaceuticals that might one day repair folding‐defective proteins. Indeed, a growing number of clinical and pre‐clinical drugs that repair ERAD and other quality control substrates have shown efficacy in various disease models. In this presentation, each of these topics will be discussed and future research directions defined.