title: Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells.
abstract: 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.
authors.affiliation: 1] Apoptosis Research Center, National University of Ireland, Galway, Ireland [2] School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: S
authors.identifier: 0000000206449752
authors.initials: S
authors.lastname: Saveljeva
authors.affiliation: 1] Apoptosis Research Center, National University of Ireland, Galway, Ireland [2] School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: S L
authors.initials: SL
authors.lastname: Mc Laughlin
authors.affiliation: 1] VIB Inflammation Research Center (IRC), Technologiepark 927, Zwijnaarde-Gent 9052, Belgium [2] Department of Biomedical Molecular Biology, VIB/Ghent University, Technologiepark 927, Zwijnaarde-Gent 9052, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: 1] Apoptosis Research Center, National University of Ireland, Galway, Ireland [2] School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: A
authors.identifier: 0000000286108375
authors.initials: A
authors.lastname: Samali
authors.affiliation: 1] VIB Inflammation Research Center (IRC), Technologiepark 927, Zwijnaarde-Gent 9052, Belgium [2] Department of Biomedical Molecular Biology, VIB/Ghent University, Technologiepark 927, Zwijnaarde-Gent 9052, Belgium.
authors.forename: M J M
authors.initials: MJ
authors.lastname: Bertrand
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D009336:Necrosis; D011494:Protein Kinases / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*
chemical_list: D008024:Ligands; D047888:Receptors, Tumor Necrosis Factor, Type I; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases