Molecular chaperones and substrate ubiquitination control the efficiency of endoplasmic reticulum-associated degradation.

The endoplasmic reticulum (ER) must contend with a large protein flux, which is especially notable in cells dedicated to secreting hormone-regulated gene products. Because of the complexity of the protein folding pathway and the potential for genetic or stochastic errors, a significant percentage of these nascent secreted proteins fail to acquire their native conformations. If these species cannot be cleared from the ER, they may aggregate, which leads to cell death. To lessen the effects of potentially toxic polypeptides, aberrant ER proteins are destroyed via a process known as ER-associated degradation (ERAD). ERAD substrates are selected by molecular chaperones and chaperone-like proteins, and prior to degradation most substrates are ubiquitin-modified. Together with the unfolded protein response, the ERAD pathway is a critical component of the protein quality control machinery in the ER. Although emerging data continue to link ERAD with human diseases, most of our knowledge of this pathway arose from studies using a model eukaryote, the yeast Saccharomyces cerevisiae. In this review, we will summarize the discoveries that led to our current understanding of this pathway, focusing primarily on experiments in yeast. We will also indicate links between ERAD and disease and emphasize future research avenues.