HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction.

Hdl Handle:
http://hdl.handle.net/10147/114676
Title:
HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction.
Authors:
Gupta, Sanjeev; Deepti, Ayswaria; Deegan, Shane; Lisbona, Fernanda; Hetz, Claudio; Samali, Afshin
Affiliation:
Apoptosis Research Centre, School of Natural Sciences, NUI Galway, Galway, Ireland.
Citation:
HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction. 2010, 8 (7):e1000410 PLoS Biol.
Journal:
PLoS biology
Issue Date:
2010
URI:
http://hdl.handle.net/10147/114676
DOI:
10.1371/journal.pbio.1000410
PubMed ID:
20625543
Abstract:
Endoplasmic 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.
Item Type:
Article
Language:
en
Keywords:
GENETICS
MeSH:
Alternative Splicing; Animals; Apoptosis; Cell Survival; Cytochromes c; Cytoprotection; DNA-Binding Proteins; Endoplasmic Reticulum; Endoribonucleases; HSP72 Heat-Shock Proteins; Humans; Membrane Potential, Mitochondrial; Mice; Models, Biological; PC12 Cells; Protein Binding; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases; RNA, Messenger; Rats; Signal Transduction; Stress, Physiological; Transcription Factors
ISSN:
1545-7885

Full metadata record

DC FieldValue Language
dc.contributor.authorGupta, Sanjeeven
dc.contributor.authorDeepti, Ayswariaen
dc.contributor.authorDeegan, Shaneen
dc.contributor.authorLisbona, Fernandaen
dc.contributor.authorHetz, Claudioen
dc.contributor.authorSamali, Afshinen
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

Related articles on PubMed

All Items in Lenus, The Irish Health Repository are protected by copyright, with all rights reserved, unless otherwise indicated.