Ca2+ mobilization-dependent reduction of the endoplasmic reticulum lumen is due to influx of cytosolic glutathione

Lizák, Beáta and Birk, Julia and Zana, Melinda and Kosztyi, Gergely and Kratschmar, Denise V. and Odermatt, Alex and Zimmermann, Richard and Geiszt, Miklós and Appenzeller-Herzog, Christian and Bánhegyi, Gábor. (2020) Ca2+ mobilization-dependent reduction of the endoplasmic reticulum lumen is due to influx of cytosolic glutathione. BMC Biology, 18 (1). p. 19.

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The lumen of the endoplasmic reticulum (ER) acts as a cellular Ca2+ store and a site for oxidative protein folding, which is controlled by the reduced glutathione (GSH) and glutathione-disulfide (GSSG) redox pair. Although depletion of luminal Ca2+ from the ER provokes a rapid and reversible shift towards a more reducing poise in the ER, the underlying molecular basis remains unclear. We found that Ca2+ mobilization-dependent ER luminal reduction was sensitive to inhibition of GSH synthesis or dilution of cytosolic GSH by selective permeabilization of the plasma membrane. A glutathione-centered mechanism was further indicated by increased ER luminal glutathione levels in response to Ca2+ efflux. Inducible reduction of the ER lumen by GSH flux was independent of the Ca2+-binding chaperone calreticulin, which has previously been implicated in this process. However, opening the translocon channel by puromycin or addition of cyclosporine A mimicked the GSH-related effect of Ca2+ mobilization. While the action of puromycin was ascribable to Ca2+ leakage from the ER, the mechanism of cyclosporine A-induced GSH flux was independent of calcineurin and cyclophilins A and B and remained unclear. Our data strongly suggest that ER influx of cytosolic GSH, rather than inhibition of local oxidoreductases, is responsible for the reductive shift upon Ca2+ mobilization. We postulate the existence of a Ca2+- and cyclosporine A-sensitive GSH transporter in the ER membrane. These findings have important implications for ER redox homeostasis under normal physiology and ER stress.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Appenzeller-Herzog, Christian and Birk, Julia and Kratschmar, Denise and Odermatt, Alex
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:BioMed Central
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Mar 2020 07:18
Deposited On:10 Mar 2020 07:18

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