ABSTRACT
The role played by N-linked oligosaccharides in the endoplasmic reticulum (ER) quality control (ERQC) of newly synthesized glycoproteins is now well characterized and essentially conserved in all eukaryotes ranging from yeast to mammals [1,2]. In the mammalian ER, the addition and removal of glucose at the A branch terminus of N-linked oligosaccharides is involved in the productive folding of glycoproteins, which is mediated through interactions with the lectinchaperones calnexin and calreticulin that recognize and bind to monoglucosylated N-glycans (Figure 11.1) (refer Chapter 8). Polypeptides that fail to adopt their native conformation are retained in the ER where they undergo multiple folding attempts. Failure to adopt the correct conformation results in their elimination from the ER through a mechanism known as ER-associated degradation (ERAD) [1-5] (Figure 11.1). ERAD is an elaborate mechanism for the elimination of misfolded proteins or misassembled protein complexes synthesized and accumulated in the ER. Polypeptides recognized as terminally misfolded are retrotranslocated out of the ER through a protein-conducting channel called the dislocon into the cytosol where they are degraded by the cytoplasmic proteasome. ATP hydrolysis is required for the retrotranslocation of ERAD substrates, which are polyubiquitinated by E3 ubiquitin ligases in the ER membrane. The N-linked sugars are removed by cytosolic peptide-N-glycanase (PNGase) before entry into the cavity of the proteasome.
