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

  • Lizák, Beáta1
  • Birk, Julia2
  • Zana, Melinda1, 3
  • Kosztyi, Gergely1
  • Kratschmar, Denise V.2
  • Odermatt, Alex2
  • Zimmermann, Richard4
  • Geiszt, Miklós1, 3
  • Appenzeller-Herzog, Christian2, 5
  • Bánhegyi, Gábor1
  • 1 Semmelweis University, Budapest, Hungary , Budapest (Hungary)
  • 2 University of Basel, Klingelbergstrasse 50, Basel, 4056, Switzerland , Basel (Switzerland)
  • 3 “Momentum” Peroxidase Enzyme Research Group of the Semmelweis University and the Hungarian Academy of Sciences, Budapest, Hungary , Budapest (Hungary)
  • 4 Saarland University, Homburg, 66421, Germany , Homburg (Germany)
  • 5 University of Basel, Spiegelgasse 5, Basel, 4051, Switzerland , Basel (Switzerland)
Published Article
BMC Biology
Springer (Biomed Central Ltd.)
Publication Date
Feb 26, 2020
DOI: 10.1186/s12915-020-0749-y
Springer Nature


BackgroundThe 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.ResultsWe 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.ConclusionsOur 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.

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