Endoplasmic Reticulum-Dependent Redox Reactions Control Endoplasmic Reticulum-Associated Degradation and Pathogen Entry

Abstract Significance: Protein misfolding within the endoplasmic reticulum (ER) is managed by an ER quality control system that retro-translocates aberrant proteins into the cytosol for proteasomal destruction. This process, known as ER-associated degradation, utilizes the action of ER redox enzymes to accommodate the disulfide-bonded nature of misfolded proteins. Strikingly, various pathogenic viruses and toxins co-opt these redox components to reach the cytosol during entry. These redox factors thus regulate critical cellular homeostasis and host?pathogen interactions. Recent Advances: Recent studies identify specific members of the protein disulfide isomerase (PDI) family, which use their chaperone and catalytic activities, in engaging both misfolded ER proteins and pathogens. Critical Issues: The precise molecular mechanism by which a dedicated PDI family member disrupts the disulfide bonds in the misfolded ER proteins and pathogens, as well as how they act to unfold these substrates to promote their ER-to-cytosol membrane transport, remain poorly characterized. Future Directions: How PDI family members distinguish folded versus misfolded ER substrates remains enigmatic. What physical characteristics surrounding a substrate's disulfide bond instruct PDI that it is mispaired or native? For the pathogens, as their disulfide bonds normally serve a critical role in providing physical support, what conformational changes experienced in the host enable their disulfide bonds to be disrupted? A combination of more rigorous biochemical and high-resolution structural studies should begin to address these questions. Antioxid. Redox Signal. 16, 809?818.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98492/1/ars%2E2011%2E4425.pd

The Ero1α-PDI Redox Cycle Regulates Retro-Translocation of Cholera Toxin

Cholera toxin moves from the ER to the cytosol to intoxicate host cells. Here we demonstrate that the redox chaperones Ero1α and PDI play crucial roles in the ER-to-cytosol translocation of the toxin

The E3 Ubiquitin Ligases Hrd1 and gp78 Bind to and Promote Cholera Toxin Retro-Translocation

Cholera toxin intoxicates cells by trafficking from the cell surface to the endoplasmic reticulum (ER) where the toxic CTA1 peptide subsequently retro-translocates to the cytosol to induce toxicity. In this study, we uncovered the ER membrane components Hrd1 and gp78 as crucial players in the ER-to-cytosol transport of CTA1