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Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells

Endoplasmic reticulum (ER) stress-induced cellular dysfunction and death is associated with several human diseases. It has been widely reported that ER stress kills through activation of the intrinsic mitochondrial apoptotic pathway. Here we demonstrate that ER stress can also induce necroptosis, an...

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Autores principales: Saveljeva, S, Mc Laughlin, S L, Vandenabeele, P, Samali, A, Bertrand, M J M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669746/
https://www.ncbi.nlm.nih.gov/pubmed/25569104
http://dx.doi.org/10.1038/cddis.2014.548
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author Saveljeva, S
Mc Laughlin, S L
Vandenabeele, P
Samali, A
Bertrand, M J M
author_facet Saveljeva, S
Mc Laughlin, S L
Vandenabeele, P
Samali, A
Bertrand, M J M
author_sort Saveljeva, S
collection PubMed
description Endoplasmic reticulum (ER) stress-induced cellular dysfunction and death is associated with several human diseases. It has been widely reported that ER stress kills through activation of the intrinsic mitochondrial apoptotic pathway. Here we demonstrate that ER stress can also induce necroptosis, an receptor-interacting protein kinase 1 (RIPK1)/RIPK3/mixed lineage kinase domain-like protein (MLKL)-dependent form of necrosis. Remarkably, we observed that necroptosis induced by various ER stressors in L929 cells is dependent on tumor necrosis factor receptor 1 (TNFR1), but occurs independently of autocrine TNF or lymphotoxin α production. Moreover, we found that repression of either TNFR1, RIPK1 or MLKL did not protect the cells from death but instead allowed a switch to ER stress-induced apoptosis. Interestingly, while caspase inhibition was sufficient to protect TNFR1- or MLKL-deficient cells from death, rescue of the RIPK1-deficient cells additionally required RIPK3 depletion, indicating a switch back to RIPK3-dependent necroptosis in caspase-inhibited conditions. The finding that ER stress also induces necroptosis may open new therapeutic opportunities for the treatment of pathologies resulting from unresolved ER stress.
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spelling pubmed-46697462015-12-08 Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells Saveljeva, S Mc Laughlin, S L Vandenabeele, P Samali, A Bertrand, M J M Cell Death Dis Original Article Endoplasmic reticulum (ER) stress-induced cellular dysfunction and death is associated with several human diseases. It has been widely reported that ER stress kills through activation of the intrinsic mitochondrial apoptotic pathway. Here we demonstrate that ER stress can also induce necroptosis, an receptor-interacting protein kinase 1 (RIPK1)/RIPK3/mixed lineage kinase domain-like protein (MLKL)-dependent form of necrosis. Remarkably, we observed that necroptosis induced by various ER stressors in L929 cells is dependent on tumor necrosis factor receptor 1 (TNFR1), but occurs independently of autocrine TNF or lymphotoxin α production. Moreover, we found that repression of either TNFR1, RIPK1 or MLKL did not protect the cells from death but instead allowed a switch to ER stress-induced apoptosis. Interestingly, while caspase inhibition was sufficient to protect TNFR1- or MLKL-deficient cells from death, rescue of the RIPK1-deficient cells additionally required RIPK3 depletion, indicating a switch back to RIPK3-dependent necroptosis in caspase-inhibited conditions. The finding that ER stress also induces necroptosis may open new therapeutic opportunities for the treatment of pathologies resulting from unresolved ER stress. Nature Publishing Group 2015-01 2015-01-08 /pmc/articles/PMC4669746/ /pubmed/25569104 http://dx.doi.org/10.1038/cddis.2014.548 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0
spellingShingle Original Article
Saveljeva, S
Mc Laughlin, S L
Vandenabeele, P
Samali, A
Bertrand, M J M
Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells
title Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells
title_full Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells
title_fullStr Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells
title_full_unstemmed Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells
title_short Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells
title_sort endoplasmic reticulum stress induces ligand-independent tnfr1-mediated necroptosis in l929 cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669746/
https://www.ncbi.nlm.nih.gov/pubmed/25569104
http://dx.doi.org/10.1038/cddis.2014.548
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