The interaction of factors required for ER associated degradation (ERAD)

Abstract

Many proteins that play critical roles in cellular physiology transit through the secretory pathway, and a significant percentage can fold slowly or inefficiently. Because unfolded proteins compromise cellular function and trigger apoptosis, it is critical that these proteins are recognized and destroyed. Fortunately, once selected by chaperones, defective secreted proteins can be removed via a process termed ER associated degradation (ERAD). During ERAD, polypeptides are delivered from the ER, ubiquitinated, and destroyed by the proteasome. By using a variety of models, many of the critical players in this pathway have been identified and their functions discerned. However, it is likely that there are substrate‐specific modifiers of ERAD and factors that act redundantly with one another that remain unknown. Because ERAD has been linked to many human diseases, we propose that ERAD modifiers might, in turn, be disease modifiers. To this end, we have used yeast‐based expression systems to dissect the ERAD pathway for disease‐causing proteins and to identify uncharacterized factors that modulate ERAD. Our studies have been complemented by in vitro systems that have allowed us to dissect at which step in the ERAD pathway specific factors act.