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Review
. 2013 Sep 1;5(9):a013185.
doi: 10.1101/cshperspect.a013185.

The mammalian endoplasmic reticulum-associated degradation system

James A Olzmann  1 , Ron R Kopito, John C Christianson
Affiliations
Review

The mammalian endoplasmic reticulum-associated degradation system

James A Olzmann et al. Cold Spring Harb Perspect Biol. .

Abstract

The endoplasmic reticulum (ER) is the site of synthesis for nearly one-third of the eukaryotic proteome and is accordingly endowed with specialized machinery to ensure that proteins deployed to the distal secretory pathway are correctly folded and assembled into native oligomeric complexes. Proteins failing to meet this conformational standard are degraded by ER-associated degradation (ERAD), a complex process through which folding-defective proteins are selected and ultimately degraded by the ubiquitin-proteasome system. ERAD proceeds through four tightly coupled steps involving substrate selection, dislocation across the ER membrane, covalent conjugation with polyubiquitin, and proteasomal degradation. The ERAD machinery shows a modular organization with central ER membrane-embedded ubiquitin ligases linking components responsible for recognition in the ER lumen to the ubiquitin-proteasome system in the cytoplasm. The core ERAD machinery is highly conserved among eukaryotes and much of our basic understanding of ERAD organization has been derived from genetic and biochemical studies of yeast. In this article we discuss how the core ERAD machinery is organized in mammalian cells.

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Figures

Figure 1.
Figure 1.
Key steps in ERAD. ERAD occurs through a series of temporally ordered steps, which include: Step 1—Recognition: Molecular chaperones and lectins within the ER lumen interact with incompletely folded or unassembled clients. These factors link substrate recognition to the dislocation machinery by binding to membrane-embedded adaptors. Step 2—Dislocation: Substrates are dislocated across the bilayer presumably through proteinaceous pores (dislocons), via a process coupled to the energy derived from ATP hydrolysis by VCP/p97. Step 3—Ubiquitination: On gaining access to the cytosol, substrates are polyubiquitinated by E3 ligases. Step 4—Degradation: Ubiquitinated substrates are degraded by cytosolic 26S proteasomes.
Figure 2.
Figure 2.
Protein adaptors within the ER membrane link substrate recognition to the dislocation apparatus. ERAD substrates (black) differ in topology, the features and location of the folding lesion, and posttranslational modification. To accommodate this diversity, the ERAD system is organized with lumenal substrate recognition factors (blue) and membrane-embedded adaptor proteins (purple) that cooperate to recruit ERAD substrates to a set of E3 ligase-coupled dislocation complexes. The dislocation complexes integrate the coupled processes of substrate ubiquitination, membrane extraction via VCP/p97, and proteolytic destruction by the 26S proteasome.
Figure 3.
Figure 3.
Models of rhomboid pseudoprotease function in ERAD. (A) Structural model of the rhomboid domain of Derlin-1 indicating key conserved features that identify it as a member of the rhomboid family. The L5 loop and TM5 have been proposed to function as a gate that controls the entry of membrane-spanning substrate domains. (B) Rearrangement of TM5 and the L5 loop could function as a gate to allow Derlin-1 to bind and destabilize substrate transmembrane domains, thereby facilitating substrate extraction by VCP/p97. Thinning of the bilayer imposed by the rhomboid structure could enhance this destabilization. (C) Alternatively, Derlin-1 could regulate ERAD machinery by catalyzing the dissociation or cycling of dislocation complexes, which may be coupled to the release of a substrate from the cytosolic face of the ER membrane.
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References

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