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dc.contributor.authorGupta, Sanjeev
dc.contributor.authorDeepti, Ayswaria
dc.contributor.authorDeegan, Shane
dc.contributor.authorLisbona, Fernanda
dc.contributor.authorHetz, Claudio
dc.contributor.authorSamali, Afshin
dc.date.accessioned2010-11-04T11:09:55Z
dc.date.available2010-11-04T11:09:55Z
dc.date.issued2010
dc.identifier.citationHSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction. 2010, 8 (7):e1000410 PLoS Biol.en
dc.identifier.issn1545-7885
dc.identifier.pmid20625543
dc.identifier.doi10.1371/journal.pbio.1000410
dc.identifier.urihttp://hdl.handle.net/10147/114676
dc.description.abstractEndoplasmic reticulum (ER) stress is a feature of secretory cells and of many diseases including cancer, neurodegeneration, and diabetes. Adaptation to ER stress depends on the activation of a signal transduction pathway known as the unfolded protein response (UPR). Enhanced expression of Hsp72 has been shown to reduce tissue injury in response to stress stimuli and improve cell survival in experimental models of stroke, sepsis, renal failure, and myocardial ischemia. Hsp72 inhibits several features of the intrinsic apoptotic pathway. However, the molecular mechanisms by which Hsp72 expression inhibits ER stress-induced apoptosis are not clearly understood. Here we show that Hsp72 enhances cell survival under ER stress conditions. The UPR signals through the sensor IRE1alpha, which controls the splicing of the mRNA encoding the transcription factor XBP1. We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. Inhibition of XBP1 mRNA splicing either by dominant negative IRE1alpha or by knocking down XBP1 specifically abrogated the inhibition of ER stress-induced apoptosis by Hsp72. Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1alpha. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1alpha in vitro, suggesting a direct regulation. Our data show that binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. These results provide a physical connection between cytosolic chaperones and the ER stress response.
dc.language.isoenen
dc.subjectGENETICSen
dc.subject.meshAlternative Splicing
dc.subject.meshAnimals
dc.subject.meshApoptosis
dc.subject.meshCell Survival
dc.subject.meshCytochromes c
dc.subject.meshCytoprotection
dc.subject.meshDNA-Binding Proteins
dc.subject.meshEndoplasmic Reticulum
dc.subject.meshEndoribonucleases
dc.subject.meshHSP72 Heat-Shock Proteins
dc.subject.meshHumans
dc.subject.meshMembrane Potential, Mitochondrial
dc.subject.meshMice
dc.subject.meshModels, Biological
dc.subject.meshPC12 Cells
dc.subject.meshProtein Binding
dc.subject.meshProtein Structure, Tertiary
dc.subject.meshProtein-Serine-Threonine Kinases
dc.subject.meshRNA, Messenger
dc.subject.meshRats
dc.subject.meshSignal Transduction
dc.subject.meshStress, Physiological
dc.subject.meshTranscription Factors
dc.titleHSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction.en
dc.typeArticleen
dc.contributor.departmentApoptosis Research Centre, School of Natural Sciences, NUI Galway, Galway, Ireland.en
dc.identifier.journalPLoS biologyen
refterms.dateFOA2018-08-22T09:44:43Z
html.description.abstractEndoplasmic reticulum (ER) stress is a feature of secretory cells and of many diseases including cancer, neurodegeneration, and diabetes. Adaptation to ER stress depends on the activation of a signal transduction pathway known as the unfolded protein response (UPR). Enhanced expression of Hsp72 has been shown to reduce tissue injury in response to stress stimuli and improve cell survival in experimental models of stroke, sepsis, renal failure, and myocardial ischemia. Hsp72 inhibits several features of the intrinsic apoptotic pathway. However, the molecular mechanisms by which Hsp72 expression inhibits ER stress-induced apoptosis are not clearly understood. Here we show that Hsp72 enhances cell survival under ER stress conditions. The UPR signals through the sensor IRE1alpha, which controls the splicing of the mRNA encoding the transcription factor XBP1. We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. Inhibition of XBP1 mRNA splicing either by dominant negative IRE1alpha or by knocking down XBP1 specifically abrogated the inhibition of ER stress-induced apoptosis by Hsp72. Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1alpha. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1alpha in vitro, suggesting a direct regulation. Our data show that binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. These results provide a physical connection between cytosolic chaperones and the ER stress response.


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