Quality control in the endoplasmic reticulum

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Abstract
Protein folding in the endoplasmic reticulum (ER) is assisted by several molecular chaperones and folding factors. These proteins are key players in the quality-control (QC) system, which regulates the transport of proteins from the ER to other compartments of the secretory pathway. The QC system works at two levels — general and protein-specific. The general level ('primary QC') applies to all proteins and involves the recognition of structural and biophysical features that are common to non-native proteins. The protein-specific level ('secondary QC') involves the recognition of individual proteins or protein families by specialized chaperones. An important factor for determining ER retention is protein stability — the lower the overall stability of a protein the more likely it is to be retained. For glycoproteins, there is a QC system that is based on the recognition of specific glycosylation intermediates of N-linked glycans. This system depends crucially on the direct interaction of the two lectin chaperones, calnexin and calreticulin, with newly synthesized glycoproteins. At the level of ER export, protein sorting at ER exit sites determines whether a protein can leave the ER. Here, export and retention signals, the effects of protein mobility in the ER and selective inclusion in ER exit sites are crucial factors. Protein folding and maturation are intrinsically error-prone processes, and a substantial fraction of proteins are degraded rapidly after synthesis. Peptides from degraded proteins are presented on the cell-surface and thereby ensure the early detection of, for example, viral infections.