Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation

The endoplasmic reticulum (ER) is the site of assembly of polypeptide chains destined for secretion or routing into various subcellular compartments. It also regulates cellular responses to stress and intracellular Ca(2+) levels. A variety of toxic insults can result in ER stress that ultimately lea...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-09, Vol.276 (36), p.33869
Main Authors: Rao, R V, Hermel, E, Castro-Obregon, S, del Rio, G, Ellerby, L M, Ellerby, H M, Bredesen, D E
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Blotting, Western
Brefeldin A - pharmacology
Calcium - metabolism
Caspase 12
Caspase 7
Caspase 9
Caspases - biosynthesis
Caspases - metabolism
Catalysis
Cell Death
Cell Line
Cell-Free System
DNA, Complementary - metabolism
Endoplasmic Reticulum - metabolism
Enzyme Activation
Humans
Mice
Mutation
Plasmids - metabolism
Precipitin Tests
Protein Transport
Recombinant Proteins - metabolism
Stress, Physiological
Subcellular Fractions
Thapsigargin - pharmacology
Transfection
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Summary:The endoplasmic reticulum (ER) is the site of assembly of polypeptide chains destined for secretion or routing into various subcellular compartments. It also regulates cellular responses to stress and intracellular Ca(2+) levels. A variety of toxic insults can result in ER stress that ultimately leads to apoptosis. Apoptosis is initiated by the activation of members of the caspase family and serves as a central mechanism in the cell death process. The present study was carried out to determine the role of caspases in triggering ER stress-induced cell death. Treatment of cells with ER stress inducers such as brefeldin-A or thapsigargin induces the expression of caspase-12 protein and also leads to translocation of cytosolic caspase-7 to the ER surface. Caspase-12, like most other members of the caspase family, requires cleavage of the prodomain to activate its proapoptotic form. Caspase-7 associates with caspase-12 and cleaves the prodomain to generate active caspase-12, resulting in increased cell death. We propose that any cellular insult that causes prolonged ER stress may induce apoptosis through caspase-7-mediated caspase-12 activation. The data underscore the involvement of ER and caspases associated with it in the ER stress-induced apoptotic process.
ISSN:0021-9258
DOI:10.1074/jbc.M102225200