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 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.
Rao
R V
RV
Buck Institute for Age Research, 8001 Redwood Blvd, Novato, California 94945, USA.
Hermel
E
E
Castro-Obregon
S
S
del Rio
G
G
Ellerby
L M
LM
Ellerby
H M
HM
Bredesen
D E
DE
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D053454:Caspase 12; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism*; D002384:Catalysis; D016923:Cell Death; D002460:Cell Line; D002474:Cell-Free System; D018076:DNA, Complementary / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D013312:Stress, Physiological; D013347:Subcellular Fractions; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection
D018076:DNA, Complementary; D011994:Recombinant Proteins; D020126:Brefeldin A; D019284:Thapsigargin; C506444:CASP12 protein, human; C505520:CASP7 protein, human; C506433:CASP9 protein, human; C506440:Casp12 protein, mouse; C505524:Casp7 protein, mouse; C506434:Casp9 protein, mouse; D053454:Caspase 12; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases; D002118:Calcium