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

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Standard

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.

In: Cell Calcium, Vol. 76, https://doi.org/10.1016/j.ceca.2018.09.005, 12.2018, p. 48-61.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Szalai, P, Parys, JB, Bultynckb, G, Christensen, SB, Nissen, P, Møller, JV & Engedal, N 2018, 'Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death', Cell Calcium, vol. 76, https://doi.org/10.1016/j.ceca.2018.09.005, pp. 48-61. https://doi.org/10.1016/j.ceca.2018.09.005

APA

Szalai, P., Parys, J. B., Bultynckb, G., Christensen, S. B., Nissen, P., Møller, J. V., & Engedal, N. (2018). Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death. Cell Calcium, 76, 48-61. [https://doi.org/10.1016/j.ceca.2018.09.005]. https://doi.org/10.1016/j.ceca.2018.09.005

Vancouver

Szalai P, Parys JB, Bultynckb G, Christensen SB, Nissen P, Møller JV et al. Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death. Cell Calcium. 2018 Dec;76:48-61. https://doi.org/10.1016/j.ceca.2018.09.005. https://doi.org/10.1016/j.ceca.2018.09.005

Author

Szalai, Paula ; Parys, Jan B. ; Bultynckb, Geert ; Christensen, Søren Brøgger ; Nissen, Poul ; Møller, Jesper Vuust ; Engedal, Nikolai. / Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death. In: Cell Calcium. 2018 ; Vol. 76. pp. 48-61.

Bibtex

@article{9e08aea73aad4b3580608f724035d020,
title = "Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death",
abstract = "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.",
keywords = "The Faculty of Health and Medical Sciences, Endoplasmic reticulum, Calcium, Unfolded Protein Response, Thapsigargin, Cell Death, Autophagy",
author = "Paula Szalai and Parys, {Jan B.} and Geert Bultynckb and Christensen, {S{\o}ren Br{\o}gger} and Poul Nissen and M{\o}ller, {Jesper Vuust} and Nikolai Engedal",
year = "2018",
month = "12",
doi = "10.1016/j.ceca.2018.09.005",
language = "English",
volume = "76",
pages = "48--61",
journal = "Cell Calcium",
issn = "0143-4160",
publisher = "Churchill Livingstone",

}

RIS

TY - JOUR

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 - The 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

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