Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death

Eukaryotic cells fold and assemble membrane and secreted proteins in the endoplasmic reticulum (ER), before delivery to other cellular compartments or the extracellular environment. Correctly folded proteins are released from the ER, and poorly folded proteins are retained until they achieve stable...

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Bibliographic Details
Published in:The American journal of pathology Vol. 185; no. 7; p. 1800
Main Authors: Hiramatsu, Nobuhiko, Chiang, Wei-Chieh, Kurt, Timothy D, Sigurdson, Christina J, Lin, Jonathan H
Format: Journal Article
Language:English
Published: United States 01.07.2015
Subjects:
Animals
Apoptosis
Awards and Prizes
eIF-2 Kinase - metabolism
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum Stress
Endoribonucleases - metabolism
Eukaryotic Cells - physiology
Humans
Mammals
Models, Biological
Molecular Chaperones - metabolism
Pathology
Protein Biosynthesis
Protein Serine-Threonine Kinases - metabolism
Signal Transduction
Societies, Medical
Unfolded Protein Response
United States
United States
ISSN:1525-2191, 1525-2191
Online Access:Get more information
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Summary:Eukaryotic cells fold and assemble membrane and secreted proteins in the endoplasmic reticulum (ER), before delivery to other cellular compartments or the extracellular environment. Correctly folded proteins are released from the ER, and poorly folded proteins are retained until they achieve stable conformations; irreparably misfolded proteins are targeted for degradation. Diverse pathological insults, such as amino acid mutations, hypoxia, or infection, can overwhelm ER protein quality control, leading to misfolded protein buildup, causing ER stress. To cope with ER stress, eukaryotic cells activate the unfolded protein response (UPR) by increasing levels of ER protein-folding enzymes and chaperones, enhancing the degradation of misfolded proteins, and reducing protein translation. In mammalian cells, three ER transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6, control the UPR. The UPR signaling triggers a set of prodeath programs when the cells fail to successfully adapt to ER stress or restore homeostasis. ER stress and UPR signaling are implicated in the pathogenesis of diverse diseases, including neurodegeneration, cancer, diabetes, and inflammation. This review discusses the current understanding in both adaptive and apoptotic responses as well as the molecular mechanisms instigating apoptosis via IRE1 and PERK signaling. We also examine how IRE1 and PERK signaling may be differentially used during neurodegeneration arising in retinitis pigmentosa and prion infection.
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ISSN:1525-2191
1525-2191
DOI:10.1016/j.ajpath.2015.03.009