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Quality control in the endoplasmic reticulum

Nature Reviews Molecular Cell Biology volume 4, pages 181–191 (2003)Cite this article

Key Points

  • 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.

Abstract

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.

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Figure 1: The effects of the endoplasmic reticulum environment on folding equilibria.
Figure 2: The calnexin/calreticulin cycle.
Figure 3: Trafficking of a cargo glycoprotein from the endoplasmic reticulum through exit sites to the Golgi complex.

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Acknowledgements

We thank A. Smith, A. Mezzacasa and E. Frickel for their critical reading of the manuscript. This work was supported by the Swiss National Science Foundation.

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Authors and Affiliations

  1. Institute of Biochemistry, Swiss Federal Institute of Technology (ETH) Zürich, Hönggerberg, Zürich, CH - 8093, Switzerland

    Lars Ellgaard & Ari Helenius

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  1. Lars Ellgaard
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Correspondence to Ari Helenius.

Related links

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DATABASES

European Bioinformatics Institute

BiP

calnexin

calreticulin

CFTR

ERp57

PDI

UDP-glucose:glycoprotein glucosyltransferase

FURTHER INFORMATION

Ari Helenius' laboratory

Lars Ellgaard's laboratory

Glossary

CONFORMATIONAL STABILITY

The conformational stability of a protein is defined as the free energy change, ΔG, for the conversion of its unfolded (denatured) form to its folded (native) form.

LECTIN

A protein that binds carbohydrates.

F-BOX PROTEIN

A protein component of a ubiquitin-ligase complex that contains an F-box domain, which is responsible for the interaction with a specific substrate protein.

UBIQUITIN LIGASE

A protein or protein complex that mediates the ubiquitylation of a substrate protein through interactions with other components of the ubiquitylation machinery.

CFTR

(Cystic fibrosis transmembrane conductance regulator). A plasma membrane Cl− channel.

CFTRΔF508

A folding-defective and principal disease-causing allele of the cystic fibrosis transmembrane conductance regulator (CFTR).

TYPE I MEMBRANE PROTEIN

A transmembrane protein that is orientated with its carboxyl terminus in the cytosol.

14-3-3 PROTEINS

A family of abundant proteins that bind to phosphoserine- and phosphothreonine-containing motifs in a sequence-specific manner.

INVARIANT CHAIN

A specific chaperone and escort protein for MHC class II molecules.

TYPE II MEMBRANE PROTEIN

A transmembrane protein that is orientated with its amino terminus in the cytosol.

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Ellgaard, L., Helenius, A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4, 181–191 (2003). https://doi.org/10.1038/nrm1052

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