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Protein homeostasis in the endoplasmic reticulum (ER) is maintained by a quality control system. When a newly synthesized ER protein misfolds, it is ultimately retrotranslocated into the cytosol, polyubiquitinated, and degraded by the proteasome, a pathway referred to as ER-associated protein degradation (ERAD). ERAD alleviates cytotoxic stress imposed by protein misfolding and is implicated in numerous diseases. ERAD is found in all eukaryotic cells but is best studied for the ERAD-L pathway in Saccharomyces cerevisiae, which disposes of misfolded glycoproteins in the ER lumen. The glycan attached to these proteins is first trimmed by glycosidases to generate a terminal α1,6-mannose residue. This residue, together with an unfolded polypeptide segment, targets the substrate to the Hrd1 complex, which is composed of the multispanning ubiquitin ligase Hrd1 and four additional proteins …