Quality control in the endoplasmic reticulum

In the assembly of a complex machine, such as a car, every essential component must conform to carefully defined specifications, and is therefore subject to stringent quality control (QC). In the cell something similar occurs — there are QC systems for practically every step that leads to the synthesis of DNA, RNA and protein molecules. As a result, the number of accumulated errors in macromolecules that are ultimately deployed by cells is extremely low. For proteins, ‘proof-reading’ occurs at the level of transcription, translation, folding and assembly. To pass the final QC checkpoints, a protein must typically have reached a correctly folded conformation. This is generally the so-called ‘native’ conformation that corresponds to the most energetically favourable state. In the case of proteins with several subunits, proper oligomeric assembly is usually necessary. If the folding and maturation process fails, a protein molecule is not transported to its final destination in the cell, and is eventually degraded. To distinguish between native and non-native protein conformations, the cell uses various sensor molecules. By definition, the sensors include the molecular chaperones, because these interact specifically with incompletely folded proteins. Molecular chaperones often have the dual role of assisting the folding process and dispatching any improperly folded proteins for destruction. The conformationsensing system also includes enzymes that selectively and covalently ‘tag’ misfolded proteins for recognition by the folding and degradation machinery. The best-known tags are ubiquitin, a small protein that is attached to lysine side chains as a degradation signal, and glucose, which is added to the N-linked glycans of glycoproteins as a retention signal in the endoplasmic reticulum (ER). In this review, we discuss the QC process that functions on newly synthesized proteins in the ER of eukaryotic cells. The stringent distinction between proteins that can or cannot be transported along the secretory pathway secures the fidelity and functionality of proteins that are expressed in the extracellular space, the plasma membrane and in the compartments that are involved in secretion and endocytosis. ER QC also regulates the degradation of those proteins that are not correctly folded. Disposal occurs by a process called ER-associated degradation (ERAD); misfolded proteins are retro-translocated from the ER into the cytosol where they are ubiquitylated and subsequently degraded by proteasomes. As ERAD has recently been reviewed in detail in this journal and elsewhere, we place our emphasis on aspects of transport regulation.