Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death

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  • Paula Szalai
  • Jan B. Parys, Instituut voor Kern- en Stralingsfysica
  • ,
  • Geert Bultynck, Instituut voor Kern- en Stralingsfysica
  • ,
  • Søren Brøgger Christensen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Københavns Universitet
  • ,
  • Poul Nissen
  • Jesper V. Møller
  • Nikolai Engedal, Universitetet i Oslo

Endoplasmic reticulum (ER) Ca2+ depletion activates the unfolded protein response (UPR), inhibits bulk autophagy and eventually induces cell death in mammalian cells. However, the extent and duration of ER Ca2+ depletion required is unknown. We instigated a detailed study in two different cell lines, using sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitors to gradually reduce ER Ca2+ levels in a controlled manner. Remarkably, UPR induction (as assessed by expression analyses of UPR-regulated proteins) and autophagy inhibition (as assessed by analyses of effects on starvation-induced bulk autophagy) required substantially higher drug concentrations than those needed to strongly decrease total ER Ca2+ levels. In fact, even when ER Ca2+ levels were so low that we could hardly detect any release of Ca2+ upon challenge with ER Ca2+ purging agents, UPR was not induced, and starvation-induced bulk autophagy was still fully supported. Moreover, although we observed reduced cell proliferation at this very low level of ER Ca2+, cells could tolerate prolonged periods (days) without succumbing to cell death. Addition of increasing concentrations of extracellular EGTA also gradually depleted the ER of Ca2+, and, as with the SERCA inhibitors, EGTA-induced activation of UPR and cell death required higher EGTA concentrations than those needed to strongly reduce ER Ca2+ levels. We conclude that ER Ca2+ depletion-induced effects on UPR, autophagy and cell death require either an extreme general depletion of ER Ca2+ levels, or Ca2+ depletion in areas of the ER that have a higher resistance to Ca2+ drainage than the bulk of the ER.

TidsskriftCell Calcium
Sider (fra-til)48-61
Antal sider14
StatusUdgivet - 1 dec. 2018

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