Protein Disulfide Isomerase Acts as a Redox-Dependent Chaperone to Unfold Cholera Toxin

Abstract

Cholera toxin is assembled from two subunits in the periplasm of Vibrio cholerae and disassembled in the analogous compartment of target cells, the lumen of the endoplasmic reticulum (ER), before a fragment of it, the A1 chain, is transported into the cytosol. We show that protein disulfide isomerase (PDI) in the ER lumen functions to disassemble and unfold the toxin once its A chain has been cleaved. PDI acts as a redox-driven chaperone; in the reduced state, it binds to the A chain and in the oxidized state it releases it. Our results explain the pathway of cholera toxin, suggest a role for PDI in retrograde protein transport into the cytosol, and indicate that PDI can act as a novel type of chaperone, whose binding and release of substrates is regulated by a redox, rather than an ATPase, cycle.

ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C

“…In this context ERdj5 may function similarly to PDI, promoting the formation, reduction or isomerization of disulfide bonds. PDI was reported to play an important role in disulfide bond reduction (unfoldase activity) before dislocation of misfolded protein (Tsai et al, 2001). The failure of two previous studies to detect ERdj5 oxidoreductase activity in .…”

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…Oxidized PDI, with active-site cysteines in the disulfide form, can act as an electron acceptor to form disulfide bonds in sulfhydryl-containing substrate proteins [157]. PDI is believed to act as a redox driven chaperone [158], although other reports have questioned the general concept of redox-regulated chaperone activity of PDI [159]. PDI is also surface associated, where it may play a role in transport of NO from S-nitrosothiols across membranes (whether directly or by maintaining surfact thiols in the reduced state is not clear) [160,161].…”

Cellular response to endoplasmic reticulum stress: a matter of life or death

“…8,9 As in yeast, glycosylation probably participates in the recognition of mammalian ERAD substrates, 73 as do BiP and PDI. 74,75 Similarly, at least some mammalian ERAD substrates may be dislocated through the Sec61 channel. 76,77 Ubiquitination machinery similar to that of yeast is also employed, and a homolog of Cdc48p, termed p97, has been shown to cooperate with mammalian homologs of Ufd1p and Npl4p in substrate dislocation.…”