Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death
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Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death. / Szalai, Paula ; Parys, Jan B.; Bultynckb, Geert; Christensen, Søren Brøgger; Nissen, Poul; Møller, Jesper Vuust; Engedal, Nikolai.
I: Cell Calcium, Bind 76, https://doi.org/10.1016/j.ceca.2018.09.005, 12.2018, s. 48-61.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death
AU - Szalai, Paula
AU - Parys, Jan B.
AU - Bultynckb, Geert
AU - Christensen, Søren Brøgger
AU - Nissen, Poul
AU - Møller, Jesper Vuust
AU - Engedal, Nikolai
PY - 2018/12
Y1 - 2018/12
N2 - Endoplasmic reticulum (ER) Ca2+ depletion activates the unfolded protein response (UPR), inhibits bulk autophagyand 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/endoplasmicreticulum Ca2+-ATPase (SERCA) inhibitors to gradually reduce ER Ca2+ levels in a controlledmanner. Remarkably, UPR induction (as assessed by expression analyses of UPR-regulated proteins) and autophagyinhibition (as assessed by analyses of effects on starvation-induced bulk autophagy) required substantiallyhigher drug concentrations than those needed to strongly decrease total ER Ca2+ levels. In fact, evenwhen 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 tolerateprolonged periods (days) without succumbing to cell death. Addition of increasing concentrations of extracellularEGTA also gradually depleted the ER of Ca2+, and, as with the SERCA inhibitors, EGTA-induced activationof 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 anextreme general depletion of ER Ca2+ levels, or Ca2+ depletion in areas of the ER that have a higher resistance toCa2+ drainage than the bulk of the ER.
AB - Endoplasmic reticulum (ER) Ca2+ depletion activates the unfolded protein response (UPR), inhibits bulk autophagyand 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/endoplasmicreticulum Ca2+-ATPase (SERCA) inhibitors to gradually reduce ER Ca2+ levels in a controlledmanner. Remarkably, UPR induction (as assessed by expression analyses of UPR-regulated proteins) and autophagyinhibition (as assessed by analyses of effects on starvation-induced bulk autophagy) required substantiallyhigher drug concentrations than those needed to strongly decrease total ER Ca2+ levels. In fact, evenwhen 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 tolerateprolonged periods (days) without succumbing to cell death. Addition of increasing concentrations of extracellularEGTA also gradually depleted the ER of Ca2+, and, as with the SERCA inhibitors, EGTA-induced activationof 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 anextreme general depletion of ER Ca2+ levels, or Ca2+ depletion in areas of the ER that have a higher resistance toCa2+ drainage than the bulk of the ER.
KW - Faculty of Health and Medical Sciences
KW - Endoplasmic reticulum
KW - Calcium
KW - Unfolded Protein Response
KW - Thapsigargin
KW - Cell Death
KW - Autophagy
U2 - 10.1016/j.ceca.2018.09.005
DO - 10.1016/j.ceca.2018.09.005
M3 - Journal article
C2 - 30261424
VL - 76
SP - 48
EP - 61
JO - Cell Calcium
JF - Cell Calcium
SN - 0143-4160
M1 - https://doi.org/10.1016/j.ceca.2018.09.005
ER -
ID: 202972622