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

ABSTRACT: BACKGROUND: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. RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Lizak B

PROVIDER: S-EPMC7043043 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Ca<sup>2+</sup> mobilization-dependent reduction of the endoplasmic reticulum lumen is due to influx of cytosolic glutathione.

Lizák Beáta B Birk Julia J Zana Melinda M Kosztyi Gergely G Kratschmar Denise V DV Odermatt Alex A Zimmermann Richard R Geiszt Miklós M Appenzeller-Herzog Christian C Bánhegyi Gábor G

BMC biology 20200226 1

<h4>Background</h4>The lumen of the endoplasmic reticulum (ER) acts as a cellular Ca<sup>2+</sup> 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 Ca<sup>2+</sup> from the ER provokes a rapid and reversible shift towards a more reducing poise in the ER, the underlying molecular basis remains unclear.<h4>Results</h4>We found that Ca<sup>2+</sup> mobilization-dependent ER ...[more]

PMID: 32101139

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Dataset Information

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

Publications

Ca<sup>2+</sup> mobilization-dependent reduction of the endoplasmic reticulum lumen is due to influx of cytosolic glutathione.

Similar Datasets

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