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

Paula Szalai, Jan B. Parys, Geert Bultynckb, Søren Brøgger Christensen, Poul Nissen, Jesper Vuust Møller, Nikolai Engedal

    7 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Article numberhttps://doi.org/10.1016/j.ceca.2018.09.005
    JournalCell Calcium
    Volume76
    Pages (from-to)48-61
    Number of pages14
    ISSN0143-4160
    DOIs
    Publication statusPublished - Dec 2018

    Keywords

    • Faculty of Health and Medical Sciences

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