Abstract
Endoplasmic reticulum (ER)-associated degradation (ERAD) is a universally important process among eukaryotic cells. ERAD is necessary to preserve cell integrity since the accumulation of defective proteins results in diseases associated with neurological dysfunction, cancer, and infections. This process involves recognition of misfolded or misassembled proteins that have been translated in association with ER membranes. Recognition of ERAD substrates leads to their extraction through the ER membrane (retrotranslocation or dislocation), ubiquitination, and destruction by cytosolic proteasomes. This review focuses on ERAD and its components as well as how viruses use this process to promote their replication and to avoid the immune response.
Highlights
Endoplasmic reticulum (ER)-associated degradation (ERAD) has been most thoroughly defined in yeast, recent studies in higher organisms have revealed the conservation of this process and its components
Further experiments indicated that drugs inducing ERAD led to recovery of Env levels and viral titers. These results suggested that the endoplasmic reticulum (ER) and mitochondria communicate through juxtaposition of their membranes, so that conditions in the mitochondria influence protein folding and ERAD
The hypothesis that CTA1 avoids ubiquitination through the absence of lysines targeted for polyubiquitination was not substantiated by mutational analysis (Rodighiero et al, 2002). These results indicate that CTA1 employs many of the typical components used for ERAD targeting, including the E3 ligase, but it is unclear how polyubiquitination and degradation of the substrate are avoided
Summary
Endoplasmic reticulum (ER)-associated degradation (ERAD) has been most thoroughly defined in yeast, recent studies in higher organisms have revealed the conservation of this process and its components. In contrast to the rhomboid proteases, the Derlins lack proteolytic activity, suggesting that these proteins bind to ERAD substrates and target them to E3 ligases for ubiquitination and to p97 for membrane extraction (Brodsky, 2012). These ubiquitin ligases are members of the cytosolic SCF (S-phase kinase-associated protein 1 (Skp1)Cullin 1 (Cul1)-F-box) family, where the F-box components of the SCF complex recognize the N-glycans of the retrotranslocated substrate, e.g., Fbs1 and Fbs2 (Yoshida, 2007).
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