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ER Stress Signaling Pathways in Cell Survival and Death

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Endoplasmic Reticulum Stress in Health and Disease

Abstract

Proteins destined for the secretory pathway are processed in the endoplasmic reticulum (ER) where a delicate balance exists between protein folding and degradation of terminally misfolded proteins. Different physiological as well as pathological stress conditions however, can lead to an imbalance between the ER protein folding capacity and protein load, giving rise to an accumulation of misfolded proteins in the ER lumen, a condition dubbed as ‘ER stress’. In an attempt to meet the increased folding demand, cells utilize a conserved signaling pathway, the unfolded protein response (UPR), which is initially charged to re-establish ER homeostasis and support survival. If this mechanism fails, persistent ER stress will eventually cause this cytoprotective UPR to switch into a cell death pathway that can activate mitochondrial apoptosis. As such, the dual function of the UPR in controlling cell fate may play a part in disease development and response to stress signals in conflicting ways. The lethal arm of the UPR may contribute to pathologies that are linked to unscheduled cell death, like diabetes and certain neurodegenerative diseases such as Alzheimer's and Parkinson’s, or be utilized by certain anticancer drugs to kill cancer cells. On the other hand, activation of the pro-survival function of the UPR may assist processes like tumorigenesis and chemoresistance, by endowing cancer cells with an increased capability to adapt to their hostile environment and to cope with cellular damage. Therefore, a better understanding of the different signaling pathways that emanate from the stressed ER and how their integration modulates cell fate decisions represents a crucial requirement to develop new strategies aimed at targeting the UPR for therapeutic purposes.

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Abbreviations

Akt:

Protein Kinase B

ATF4/6:

Activating Transcription Factor 4/6

ATP:

Adenosine Triphosphate

Bax:

Bcl-2 associated X protein

Bak:

Bcl-2 antagonist/killer

Bcl-2:

B-cell lymphoma 2

BH3:

Bcl-2 Homology 3

BI-1:

Bax inhibitor 1

Bim:

Bcl2-interacting mediator of cell death

BiP:

immunoglobulin heavy chain-Binding Protein

Ca2+ :

Calcium

CHOP:

C/EBP Homologous Protein

DKO:

Double Knock Out

eIF2α:

eukaryotic Initiation Factor-2α

ER:

Endoplasmic Reticulum

ERAD:

ER Associated Degradation

ERO1:

Endoplasmic Reticulum Oxidoreductin 1

GADD34:

Growth Arrest and DNA Damage protein 34

GRP78/94:

Glucose Regulated protein 78/94P

IP3R:

Inositol 1,4,5-trisphosphate Receptor

IP3:

Inositol trisphosphate

IRE1:

Inositol Requiring Enzyme 1

JNK:

c-Jun N-terminal Kinase

KEAP1:

Kelch-like Ech-Associated Protein 1

MAMs:

Mitochondria Associated ER Membranes

MAPK:

Mitogen Activated Protein Kinase

MOMP:

Mitochondrial Outer Membrane Permeabilization

Nrf2:

Nuclear factor-E2-related factor 2

MEF:

Murine Embryonic Fibroblast

MOMP:

Mitochondrial Outer Membrane Permeabilization

MFN2:

Mitofusin 2

PDI:

Protein Disulphide Isomerase

PERK:

double stranded RNA-activated protein kinase (PKR)—like ER Kinase

PI3K:

Phosphatidylinositol-3-Kinase

RIDD:

Regulated IRE1 Dependent Decay

ROS:

Reactive Oxygen Species

S1/2P:

Site 1/2 Protease

SERCA:

Sarco/Endoplasmic Reticulum Ca2+ ATPase

S1T:

Truncated SERCA1

Sig-1R:

Sigma-1 receptor

TG:

Thapsigargin

TM:

Tunicamycin

TRAF2:

Tumor necrosis factor receptor (TNFR) Associated Factor 2

UPR:

Unfolded Protein Response

XBP1u/s:

XBP1 unspliced/spliced

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  1. Cell Death Research & Therapy Unit, Department of Cellular and Molecular Medicine, Catholic University of Leuven, Leuven, Belgium

    Tom Verfaillie & Patrizia Agostinis

  2. Apoptosis Research Center, National University of Ireland, Galway, Ireland

    Richard Jäger & Afshin Samali

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    Patrizia Agostinis

  2. School of Natural Science, Department of Biochemistry, NUI Galway, University Road, Galway, Ireland

    Samali Afshin

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Verfaillie, T., Jäger, R., Samali, A., Agostinis, P. (2012). ER Stress Signaling Pathways in Cell Survival and Death. In: Agostinis, P., Afshin, S. (eds) Endoplasmic Reticulum Stress in Health and Disease. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4351-9_3

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