| Elimination of misfolded proteins from the endoplasmic reticulum (ER) occurs largely through the ER-associated degradation (ERAD) pathway and is an important physiological adaptation to ER stress. After insertion into the lumen of the ER, glycoproteins that fail to fold properly are destined for degradation. Through a process termed retro-translocation, misfolded proteins are deposited into the cytosol from the ER, where ubiquitination, deglycosylation, and proteasomal proteolysis lead to their degradation. Derlin-1 (Der1-like protein) corresponds to a homologue of yeast Der1p, a protein identified in a genetic screen for components required for the degradation of misfolded ER luminal proteins (1). Like yeast Der1p, mammalian Derlin-1 is an ER protein that is predicted to have four transmembrane segments with both the amino and carboxy termini exposed to the cytoplasmic compartment (2-4). Derlin-1 appears to be a central, evolutionarily conserved membrane component of the retro-translocation machinery associated with the ERAD pathway. Indeed, studies have shown that Derlin-1 expression is transcriptionally upregulated in response to ER stress (5-7) and associates with ER-anchored ubiquitin ligases, such as HRD1 and gp78/AMFR, via binding to p97/VCP and VCP-interacting membrane protein (VIMP) (5,8). |
