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Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes

BACKGROUND: Myriad challenges to the proper folding and structural maturation of secretory pathway client proteins in the endoplasmic reticulum (ER) — a condition referred to as “ER stress” — activate intracellular signaling pathways termed the unfolded protein response (UPR). SCOPE OF REVIEW: Throu...

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Autores principales: Ghosh, Rajarshi, Colon-Negron, Kevin, Papa, Feroz R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768499/
https://www.ncbi.nlm.nih.gov/pubmed/31500832
http://dx.doi.org/10.1016/j.molmet.2019.06.012
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author Ghosh, Rajarshi
Colon-Negron, Kevin
Papa, Feroz R.
author_facet Ghosh, Rajarshi
Colon-Negron, Kevin
Papa, Feroz R.
author_sort Ghosh, Rajarshi
collection PubMed
description BACKGROUND: Myriad challenges to the proper folding and structural maturation of secretory pathway client proteins in the endoplasmic reticulum (ER) — a condition referred to as “ER stress” — activate intracellular signaling pathways termed the unfolded protein response (UPR). SCOPE OF REVIEW: Through executing transcriptional and translational programs the UPR restores homeostasis in those cells experiencing manageable levels of ER stress. But the UPR also actively triggers cell degeneration and apoptosis in those cells that are encountering ER stress levels that exceed irremediable thresholds. Thus, UPR outputs are “double-edged”. In pancreatic islet β-cells, numerous genetic mutations affecting the balance between these opposing UPR functions cause diabetes mellitus in both rodents and humans, amply demonstrating the principle that the UPR is critical for the proper functioning and survival of the cell. MAJOR CONCLUSIONS: Specifically, we have found that the UPR master regulator IRE1α kinase/endoribonuclease (RNase) triggers apoptosis, β-cell degeneration, and diabetes, when ER stress reaches critical levels. Based on these mechanistic findings, we find that novel small molecule compounds that inhibit IRE1α during such “terminal” UPR signaling can spare ER stressed β-cells from death, perhaps affording future opportunities to test new drug candidates for disease modification in patients suffering from diabetes.
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spelling pubmed-67684992019-10-07 Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes Ghosh, Rajarshi Colon-Negron, Kevin Papa, Feroz R. Mol Metab Review BACKGROUND: Myriad challenges to the proper folding and structural maturation of secretory pathway client proteins in the endoplasmic reticulum (ER) — a condition referred to as “ER stress” — activate intracellular signaling pathways termed the unfolded protein response (UPR). SCOPE OF REVIEW: Through executing transcriptional and translational programs the UPR restores homeostasis in those cells experiencing manageable levels of ER stress. But the UPR also actively triggers cell degeneration and apoptosis in those cells that are encountering ER stress levels that exceed irremediable thresholds. Thus, UPR outputs are “double-edged”. In pancreatic islet β-cells, numerous genetic mutations affecting the balance between these opposing UPR functions cause diabetes mellitus in both rodents and humans, amply demonstrating the principle that the UPR is critical for the proper functioning and survival of the cell. MAJOR CONCLUSIONS: Specifically, we have found that the UPR master regulator IRE1α kinase/endoribonuclease (RNase) triggers apoptosis, β-cell degeneration, and diabetes, when ER stress reaches critical levels. Based on these mechanistic findings, we find that novel small molecule compounds that inhibit IRE1α during such “terminal” UPR signaling can spare ER stressed β-cells from death, perhaps affording future opportunities to test new drug candidates for disease modification in patients suffering from diabetes. Elsevier 2019-09-06 /pmc/articles/PMC6768499/ /pubmed/31500832 http://dx.doi.org/10.1016/j.molmet.2019.06.012 Text en © 2019 Published by Elsevier GmbH. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Review
Ghosh, Rajarshi
Colon-Negron, Kevin
Papa, Feroz R.
Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes
title Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes
title_full Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes
title_fullStr Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes
title_full_unstemmed Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes
title_short Endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes
title_sort endoplasmic reticulum stress, degeneration of pancreatic islet β-cells, and therapeutic modulation of the unfolded protein response in diabetes
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768499/
https://www.ncbi.nlm.nih.gov/pubmed/31500832
http://dx.doi.org/10.1016/j.molmet.2019.06.012
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