Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β

T Nakagawa, H Zhu, N Morishima, E Li, J Xu… - Nature, 2000 - nature.com
T Nakagawa, H Zhu, N Morishima, E Li, J Xu, BA Yankner, J Yuan
Nature, 2000nature.com
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 (refs,),
mediate signal transduction downstream of death receptors located on the plasma
membrane. Others, such as caspase-9 (ref.), mediate apoptotic signals after mitochondrial …
Abstract
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 (refs , ), mediate signal transduction downstream of death receptors located on the plasma membrane. Others, such as caspase-9 (ref. ), 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-β protein but not by staurosporine or trophic factor deprivation. Thus, caspase-12 mediates an ER-specific apoptosis pathway and may contribute to amyloid-β neurotoxicity.
nature.com