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.; Bultynck, Geert; Christensen, Søren Brøgger; Nissen, Poul; Møller, Jesper V.; Engedal, Nikolai.

I: Cell Calcium, Bind 76, 01.12.2018, s. 48-61.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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

Bibtex

@article{691b4b445a9e4cc282e6b4045268690f,
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 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.",
keywords = "Autophagy, BIP, CALCIUM, Cell death, ENDOPLASMIC-RETICULUM STRESS, ER Ca2+ depletion, HOMEOSTASIS, MITOCHONDRIA, PERMEABILITY TRANSITION PORE, PERTURBATION, RECEPTOR, RESISTANCE, SERCA, THAPSIGARGIN-INDUCED APOPTOSIS, Thapsigargin, Unfolded protein response",
author = "Paula Szalai and Parys, {Jan B.} and Geert Bultynck and Christensen, {S{\o}ren Br{\o}gger} and Poul Nissen and M{\o}ller, {Jesper V.} and Nikolai Engedal",
year = "2018",
month = dec,
day = "1",
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 - Bultynck, Geert

AU - Christensen, Søren Brøgger

AU - Nissen, Poul

AU - Møller, Jesper V.

AU - Engedal, Nikolai

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

KW - Autophagy

KW - BIP

KW - CALCIUM

KW - Cell death

KW - ENDOPLASMIC-RETICULUM STRESS

KW - ER Ca2+ depletion

KW - HOMEOSTASIS

KW - MITOCHONDRIA

KW - PERMEABILITY TRANSITION PORE

KW - PERTURBATION

KW - RECEPTOR

KW - RESISTANCE

KW - SERCA

KW - THAPSIGARGIN-INDUCED APOPTOSIS

KW - Thapsigargin

KW - Unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=85053809226&partnerID=8YFLogxK

U2 - 10.1016/j.ceca.2018.09.005

DO - 10.1016/j.ceca.2018.09.005

M3 - Journal article

C2 - 30261424

AN - SCOPUS:85053809226

VL - 76

SP - 48

EP - 61

JO - Cell Calcium

JF - Cell Calcium

SN - 0143-4160

ER -