One step at a time: endoplasmic reticulum-associated degradation

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Abstract
Endoplasmic reticulum (ER)-associated degradation (ERAD) is a secretory protein quality control process that results in the removal of aberrant proteins from the ER. ERAD substrates are selected by molecular chaperones that identify proteins that might be unable to fold, that fold slowly or contain a misfolded domain, or those that lack specific protein partners. Nearly all ERAD substrates are modified with ubiquitin, a 76 amino-acid peptide that helps target proteins to the proteasome. Specific E3 ubiquitin ligases are required for ERAD and reside in or near the ER membrane. ERAD substrates are degraded by the proteasome, a large multi-catalytic protease that resides in the cytoplasm. Although integral membrane proteins in the ER can readily access the proteasome, soluble ERAD substrates (that reside within the lumen) must be retrotranslocated or dislocated from the ER to the cytoplasm before they are degraded. The ERAD pathway is conserved from yeast to humans, and indeed many of the factors that contribute to this pathway were first identified in the yeast Saccharomyces cerevisiae. A growing number of links between the ERAD pathway and human diseases have been identified.