Flagging and docking: dual roles for N-glycans in protein quality control and cellular proteostasis

Nascent polypeptides entering the endoplasmic reticulum (ER) are covalently modified with pre-assembled oligosaccharides. The terminal glucose and mannose residues are immediately removed after transfer of the oligosaccharide onto newly synthesized polypeptides. This processing determines whether the polypeptide will be retained in the ER, transported along the secretory pathway, or dislocated across the ER membrane for destruction. New avenues of research and some issues of controversy have recently been opened by the discovery that lectin–oligosaccharide interactions stabilize supramolecular complexes between regulators of ER-associated degradation (ERAD). In this Opinion article, we propose a unified model that depicts carbohydrates acting both as flags signaling the fitness of a maturing protein and as docking sites that regulate the assembly and stability of the ERAD machinery.