HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction.
Affiliation
Apoptosis Research Centre, School of Natural Sciences, NUI Galway, Galway, Ireland.Issue Date
2010Keywords
GENETICSMeSH
Alternative SplicingAnimals
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
Metadata
Show full item recordCitation
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 biologyDOI
10.1371/journal.pbio.1000410PubMed ID
20625543Abstract
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
ArticleLanguage
enISSN
1545-7885ae974a485f413a2113503eed53cd6c53
10.1371/journal.pbio.1000410
Scopus Count
Collections
Related articles
- Cytoplasmic IRE1alpha-mediated XBP1 mRNA splicing in the absence of nuclear processing and endoplasmic reticulum stress.
- Authors: Back SH, Lee K, Vink E, Kaufman RJ
- Issue date: 2006 Jul 7
- ER stress and distinct outputs of the IRE1α RNase control proliferation and senescence in response to oncogenic Ras.
- Authors: Blazanin N, Son J, Craig-Lucas AB, John CL, Breech KJ, Podolsky MA, Glick AB
- Issue date: 2017 Sep 12
- Peptides derived from the bifunctional kinase/RNase enzyme IRE1α modulate IRE1α activity and protect cells from endoplasmic reticulum stress.
- Authors: Bouchecareilh M, Higa A, Fribourg S, Moenner M, Chevet E
- Issue date: 2011 Sep
- Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway.
- Authors: Namba T, Chu K, Kodama R, Byun S, Yoon KW, Hiraki M, Mandinova A, Lee SW
- Issue date: 2015 Aug 21
- The molecular mechanisms of XBP-1 gene silencing on IRE1α-TRAF2-ASK1-JNK pathways in oral squamous cell carcinoma under endoplasmic reticulum stress.
- Authors: Chen H, Yang H, Pan L, Wang W, Liu X, Ren X, Liu Y, Liu W, Zhang Y, Jiang L, Li K, Zhang B, Wang LX
- Issue date: 2016 Feb