REVIEWS 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 strin- gent 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 pro- tein molecules 1–5 . As a result, the number of accumu- lated 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 gener- ally 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 pro- teins. Molecular chaperones often have the dual role of assisting the folding process and dispatching any improp- erly folded proteins for destruction. The conformation- sensing system also includes enzymes that selectively and covalently ‘tag’ misfolded proteins for recogni- tion 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 6 , and glucose, which is added to the N-linked glycans of glycoproteins as a retention signal in the endoplasmic reticulum (ER) 7,8 . In this review, we discuss the QC process that func- tions 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 functional- ity of proteins that are expressed in the extracellular space, the plasma membrane and in the compart- ments that are involved in secretion and endocytosis. ER QC also regulates the degradation of those pro- teins that are not correctly folded 9 . 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 sub- sequently degraded by proteasomes. As ERAD has recently been reviewed in detail in this journal 10 and elsewhere 11,12 , we place our emphasis on aspects of transport regulation. Protein folding and quality control in the ER The ER provides an environment that is optimized for protein folding and maturation. Like the lumen of other organelles of the secretory pathway (BOX 1), the ER lumen is extracytosolic and is therefore topologically equivalent to the extracellular space. Consequently, the milieu of the ER differs from that of the cytosol with QUALITY CONTROL IN THE ENDOPLASMIC RETICULUM Lars Ellgaard and Ari Helenius The endoplasmic reticulum (ER) has a quality-control system for ‘proof-reading’ newly synthesized proteins, so that only native conformers reach their final destinations. Non-native conformers and incompletely assembled oligomers are retained, and, if misfolded persistently, they are degraded. As a large fraction of ER-synthesized proteins fail to fold and mature properly, ER quality control is important for the fidelity of cellular functions. Here, we discuss recent progress in understanding the conformation-specific sorting of proteins at the level of ER retention and export. NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 4 | MARCH 2003 | 181 Institute of Biochemistry, Swiss Federal Institute of Technology (ETH) Zürich, Hönggerberg, CH – 8093 Zürich, Switzerland. Correspondence to A.H. e-mail: ari.helenius@bc.biol.ethz.ch doi:10.1038/nrm1052 © 2003 Nature Publishing Group