Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-[beta].
Nakagawa, Toshiyuki *; Zhu, Hong *; Morishima, Nobuhiro +; Li, En ++; Xu, Jin [S]; Yankner, Bruce A. [S]; Yuan, Junying *
[Letter]
Nature.
403(6765):98-103, January 6, 2000.
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Apoptosis, or cellular suicide, is important for normal development and tissue homeostasis, but too much or too little apoptosis can also cause disease 1,2. The family of cysteine proteases, the so-called caspases, are critical mediators of programmed cell death 3, and thus far 14 family members have been identified. Some of these, such as caspase-8 (refs 4, 5), mediate signal transduction downstream of death receptors located on the plasma membrane. Others, such as caspase-9 (ref. 6), mediate apoptotic signals after mitochondrial damage. Stress in the endoplasmic reticulum (ER) can also result in apoptosis 7. 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.
(C) 2000 Nature Publishing Group