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One step at a time: endoplasmic reticulum-associated degradation

Nature Reviews Molecular Cell Biology volume 9, pages 944–957 (2008)Cite this article

Key Points

  • Endoplasmic reticulum (ER)-associated degradation (ERAD) is a secretory protein quality control process that results in the removal of aberrant proteins from the ER.

  • ERAD substrates are selected by molecular chaperones that identify proteins that might be unable to fold, that fold slowly or contain a misfolded domain, or those that lack specific protein partners.

  • Nearly all ERAD substrates are modified with ubiquitin, a 76 amino-acid peptide that helps target proteins to the proteasome. Specific E3 ubiquitin ligases are required for ERAD and reside in or near the ER membrane.

  • ERAD substrates are degraded by the proteasome, a large multi-catalytic protease that resides in the cytoplasm. Although integral membrane proteins in the ER can readily access the proteasome, soluble ERAD substrates (that reside within the lumen) must be retrotranslocated or dislocated from the ER to the cytoplasm before they are degraded.

  • The ERAD pathway is conserved from yeast to humans, and indeed many of the factors that contribute to this pathway were first identified in the yeast Saccharomyces cerevisiae.

  • A growing number of links between the ERAD pathway and human diseases have been identified.

Abstract

Protein folding in the endoplasmic reticulum (ER) is monitored by ER quality control (ERQC) mechanisms. Proteins that pass ERQC criteria traffic to their final destinations through the secretory pathway, whereas non-native and unassembled subunits of multimeric proteins are degraded by the ER-associated degradation (ERAD) pathway. During ERAD, molecular chaperones and associated factors recognize and target substrates for retrotranslocation to the cytoplasm, where they are degraded by the ubiquitin–proteasome machinery. The discovery of diseases that are associated with ERAD substrates highlights the importance of this pathway. Here, we summarize our current understanding of each step during ERAD, with emphasis on the factors that catalyse distinct activities.

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Figure 1: A step-by-step illustration of endoplasmic reticulum-associated degradation.
Figure 2: N-linked glycosylation and the degradation of glycosylated proteins.

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Acknowledgements

Work in the laboratory of J.L.B. on ERAD is supported by grants from the National Institutes of Health and the Cystic Fibrosis Foundation. We thank K. Nakatsukasa for insightful discussions and comments on the manuscript, and we apologize to those researchers whose publications we could not include owing to space limitations.

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  1. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, 15260, Pennsylvania, USA

    Shruthi S. Vembar & Jeffrey L. Brodsky

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Correspondence to Jeffrey L. Brodsky.

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Glossary

Lectin-like domain

Lectins are sugar-binding proteins that either bind to soluble carbohydrate molecules or to carbohydrate moieties in glycoproteins. Lectin-like domains are found in a wide range of proteins that are involved in protein–protein, protein–lipid and protein–nucleic acid interactions.

Thioredoxin-like

Thioredoxins are disulphide-containing proteins that regulate the redox status of the cell and have a role in diverse oxidative cellular processes. The thioredoxin-like domain typically adopts a two- or three-layer β-sandwich structure and contains a conserved Cys-X-X-Cys active-site motif.

UBL domain

(Ubiquitin-like domain). A non-enzymatic domain that resembles ubiquitin in structure. UBL domain-containing proteins might have a role in the recruitment of ubiquitylated substrates to the 26S proteasome.

RING domain

A Cys-rich tandem zinc-finger domain of 40–60 amino acids that is found in the RING E3 enzymes, a main class of E3 ubiquitin ligases.

HECT domain

(Homologous to E6AP C terminus domain). A domain in the second largest class of E3 ubiquitin ligases. In contrast to RING ligases, HECT-domain ligases form an essential thioester intermediate with ubiquitin as it is transferred from the E2 enzyme to the substrate.

SCF E3 complex

(S-phase-kinase-associated protein-1 (SKP1)–cullin–F-box E3 complex). The third largest class of E3 ubiquitin ligases. The cullin component of the SCF complex forms a scaffold and organizes substrate receptor and E2 recruitment modules at its N and C termini, respectively. Substrates are recruited to cullin by SKP1 and various F-box proteins, which regulate substrate specificity.

AAA+ ATPase

(ATPases associated with diverse cellular activities). An ATP-hydrolyzing enzyme that contains one or two conserved ATP-binding domains, which are in turn comprised of conserved A and B motifs. AAA+ ATPases assemble into oligomeric assemblies (often hexamers) that form a ring-shaped structure with a central pore.

UBX domian

(Ubiquitin-regulatory 'X' domain). An ∼80 amino-acid domain that is found at the C terminus of ubiquitin-regulatory proteins. The UBX domain is a general CDC48-interaction module.

UBA domain

(Ubiquitin-association domain). A domain of ∼45 amino acids that adopts a structure comprised of a three α-helical bundle. The domain binds to ubiquitin through a conserved hydrophobic surface patch.

Autophagosome

A double-membrane vesicle that is formed from elements of the cytoplasm and other organelles; it fuses with the vacuole or lysosome, in which the autophagosomal contents are subject to degradation.

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Vembar, S., Brodsky, J. One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9, 944–957 (2008). https://doi.org/10.1038/nrm2546

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