Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta.
Apoptosis, or cellular suicide, is important for normal development and tissue homeostasis, but too much or too little apoptosis can also cause disease. The family of cysteine proteases, the so- called caspases, are critical mediators of programmed cell death, and thus far 14 family members have been identified. Some of these, such as caspase-8, mediate signal transduction downstream of death receptors located on the plasma membrane. Others, such as caspase-9, mediate apoptotic signals after mitochondrial damage. Stress in the endoplasmic reticulum (ER) can also result in apoptosis. Here we show that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals. Mice that are deficient in caspase-12 are resistant to ER stress-induced apoptosis, but their cells undergo apoptosis in response to other death stimuli. Furthermore, we show that caspase-12-deficient cortical neurons are defective in apoptosis induced by amyloid-beta protein but not by staurosporine or trophic factor deprivation. Thus, caspase-12 mediates an ER-specific apoptosis pathway and may contribute to amyloid-beta neurotoxicity.
Nakagawa
T
T
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zhu
H
H
Morishima
N
N
Li
E
E
Xu
J
J
Yankner
B A
BA
Yuan
J
J
D000544:Alzheimer Disease / Q000201:enzymology / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D053454:Caspase 12; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D003603:Cytotoxins / Q000378:metabolism / Q000633:toxicity; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D009474:Neurons / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D013950:Thymus Gland / Q000166:cytology; D014415:Tunicamycin / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D003603:Cytotoxins; D014415:Tunicamycin; C506444:CASP12 protein, human; C506440:Casp12 protein, mouse; C506443:Casp12 protein, rat; D053454:Caspase 12; D020169:Caspases