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PMID:20625543

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Citation

Gupta, S, Deepti, A, Deegan, S, Lisbona, F, Hetz, C and Samali, A (2010) HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction. PLoS Biol. 8:e1000410

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.

Links

PubMed PMC2897763 Online version:10.1371/journal.pbio.1000410

Keywords

Alternative Splicing/genetics; Animals; Apoptosis; Cell Survival; Cytochromes c/secretion; Cytoprotection; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Endoplasmic Reticulum/metabolism; Endoplasmic Reticulum/pathology; Endoribonucleases/metabolism; HSP72 Heat-Shock Proteins/chemistry; HSP72 Heat-Shock Proteins/metabolism; Humans; Membrane Potential, Mitochondrial; Mice; Models, Biological; PC12 Cells; Protein Binding; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases/metabolism; RNA, Messenger/genetics; RNA, Messenger/metabolism; Rats; Signal Transduction; Stress, Physiological; Transcription Factors/genetics; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ERN1

involved_in

GO:0070054: mRNA splicing, via endonucleolytic cleavage and ligation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P17861)

Seeded From UniProt

complete

HUMAN:HS71A

involved_in

GO:1902380: positive regulation of endoribonuclease activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:O75460)

Seeded From UniProt

complete

HUMAN:HS71A

involved_in

GO:0033120: positive regulation of RNA splicing

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P17861)

Seeded From UniProt

complete

HUMAN:HS71A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75460

F

Seeded From UniProt

complete

RAT:XBP1

involved_in

GO:1902236: negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ERN1

enables

GO:0030544: Hsp70 protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P0DMV8

F

Seeded From UniProt

complete

HUMAN:ERN1

involved_in

GO:0070054: mRNA splicing, via endonucleolytic cleavage and ligation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_input:(UniProtKB:P17861)

Seeded From UniProt

complete

HUMAN:ERN1

involved_in

GO:0034620: cellular response to unfolded protein

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HS71A

involved_in

GO:1902236: negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HS71A

involved_in

GO:1901029: negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HS71A

involved_in

GO:1902380: positive regulation of endoribonuclease activity

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:O75460)

Seeded From UniProt

complete

HUMAN:HS71A

involved_in

GO:0033120: positive regulation of RNA splicing

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P17861)

Seeded From UniProt

complete

HUMAN:HS71A

involved_in

GO:0034620: cellular response to unfolded protein

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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