Abstract
Apoptosis, or cellular suicide, is important for normal development and tissue homeostasis, but too much or too little apoptosis can also cause disease1,2. The family of cysteine proteases, the so-called caspases, are critical mediators of programmed cell death3, 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 apoptosis7. 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.
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Acknowledgements
We thank Y.-k. Jung and B. Hyman for helpful suggestions; A. Yagi for pMCIDT-A; T. Noda for PGK-neo plasmids; J. L. Goldstein for anti-caspase-3; T. Rapoport for anti-TRAPα; S. Nagata for W4 cells; M. Yuan for technical help in the preparation of Aβ, and S.-J. Kang for providing caspase-11 mutant mice. This work was supported in part by grants from Hoechst-Marion-Roussel and Harvard Medical School project (to J.Y.) and from Human Frontier Science Program Organization and TOYOBO Biotechnology Foundation (to T.N.).
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Nakagawa, T., Zhu, H., Morishima, N. et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 403, 98–103 (2000). https://doi.org/10.1038/47513
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DOI: https://doi.org/10.1038/47513
