Probing the redox state of the ER Free

Protein homeostasis in the ER is strongly linked to the formation of native disulfide bonds during protein folding, which also requires thiol-disulfide exchange reactions that are catalyzed by members of the protein disulfide isomerase (PDI) family. Glutathione (GSH) maintains a fraction of PDIs in the reduced for, and GSH-mediated reduction results in the formation of its dimeric oxidised form glutathione disulfide (GSSG). The GSH:GSSG ratio is an established indicator of intracellular redox conditions and is considerably lower in the ER than in the cytosol. On the basis of this, possible oxidising functions of GSSG in the ER have been suggested. However, the actual oxidative capacity of the glutathione redox buffer – the electrochemical reduction potential of GSH–GSSG (E_GSH) – in the ER is not known. On page 1604, Christian Appenzeller-Herzog and colleagues report the development of a GSH-specific ER-targeted redox sensor that allows them to quantify the redox potential of GSH. They determine E_GSH in the ER of HeLa cells as −208±4 mV, which is not sufficiently oxidising to maintain the known redox state of PDIs, suggesting that GSSG does not actively facilitate oxidative protein folding in the ER. Taken together, their data demonstrate that this sensor is an important tool to determine the reduction potential of GSH in vivo and could also be useful for investigating the ER redox state under pathological conditions involving ER stress.