Molecular chaperones and substrate ubiquitination control the efficiency of endoplasmic reticulum-associated degradation

Abstract

The endoplasmic reticulum (ER) must contend with a large protein flux, which is especially notable in cells dedicated to secreting hormone-regulated gene products. Because of the complexity of the protein folding pathway and the potential for genetic or stochastic errors, a significant percentage of these nascent secreted proteins fail to acquire their native conformations. If these species cannot be cleared from the ER, they may aggregate, which leads to cell death. To lessen the effects of potentially toxic polypeptides, aberrant ER proteins are destroyed via a process known as ER-associated degradation (ERAD). ERAD substrates are selected by molecular chaperones and chaperone-like proteins, and prior to degradation most substrates are ubiquitin-modified. Together with the unfolded protein response, the ERAD pathway is a critical component of the protein quality control machinery in the ER. Although emerging data continue to link ERAD with human diseases, most of our knowledge of this pathway arose from studies using a model eukaryote, the yeast Saccharomyces cerevisiae. In this review, we will summarize the discoveries that led to our current understanding of this pathway, focusing primarily on experiments in yeast. We will also indicate links between ERAD and disease and emphasize future research avenues.

Figure 1

The Hsp70 ATPase cycle. (A) An unfolded polypeptide is delivered by an Hsp40 co-chaperone to Hsp70 that is in an ATP-bound, open (low-affinity) conformation. (B) Hsp40 interaction accelerates ATP hydrolysis by the Hsp70, resulting in high-affinity polypeptide binding by the Hsp70, which is now in the ADP-bound conformation. (C) Nucleotide exchange factors (NEFs) stimulate ATP rebinding by Hsp70, concomitant with a shift back to the open conformation and release of ADP and the polypeptide from the Hsp70. Folding may either occur spontaneously or be catalysed by other chaperones (not shown).

Figure 2

A synergistic approach to protein conformational disease treatment. A misfolded lesion (black star) in an endoplasmic reticulum membrane protein may lead to destruction of that protein by the ER-associated degradation (ERAD) quality control pathway, resulting in disease. Blocking the ubiquitination machinery (A), either generally or by inhibiting a specific component unique to a particular ERAD substrate, may prevent degradation. Additionally, chemical modulators (B) can favour a folding-competent state and increase protein stability. In combination, these approaches could have a synergistic benefit in the treatment of ERAD-linked diseases.