Abstract
Nascent polypeptides emerging into the lumen of the endoplasmic reticulum (ER) are N-glycosylated on asparagines in Asn-Xxx-Ser/Thr motifs. Processing of the core oligosaccharide eventually determines the fate of the associated polypeptide by regulating entry into and retention by the calnexin chaperone system, or extraction from the ER folding environment for disposal. Recent advances have shown that at least two N-glycans are necessary for protein access to the calnexin chaperone system and that polypeptide cycling in the system is a rather rare event, which, for folding-defective polypeptides, is activated only upon persistent misfolding. Additionally, dismantling of the polypeptide-bound N-glycan interrupts futile folding attempts, and elicits preparation of the misfolded chain for dislocation into the cytosol and degradation.