Mechanistic insights into ER-associated protein degradation

Misfolded proteins of the endoplasmic reticulum (ER) are discarded by a conserved process, called ER-associated protein degradation (ERAD). ERAD substrates are retro-translocated into the cytosol, polyubiquitinated, extracted from the ER membrane, and ultimately degraded by the proteasome. Recent in vitro experiments with purified components have given insight into the mechanism of ERAD. ERAD substrates with misfolded luminal or intramembrane domains are moved across the ER membrane through a channel formed by the multispanning ubiquitin ligase Hrd1. Following polyubiquitination, substrates are extracted from the membrane by the Cdc48/p97 ATPase complex and transferred to the proteasome. We discuss the molecular mechanism of these processes and point out remaining open questions.