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Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death

2004; Rockefeller University Press; Volume: 165; Issue: 3 Linguagem: Inglês

10.1083/jcb.200310015

1540-8140

Junichi Hitomi, Taiichi Katayama, Yutaka Eguchi, Takashi Kudo, Manabu Taniguchi, Yoshihisa Koyama, Takayuki Manabe, Satoru Yamagishi, Yoshio Bandô, Kazunori Imaizumi, Yoshihide Tsujimoto, Masaya Tohyama,

Autophagy in Disease and Therapy

Recent studies have suggested that neuronal death in Alzheimer's disease or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Although caspase-12 has been implicated in ER stress-induced apoptosis and amyloid-beta (Abeta)-induced apoptosis in rodents, it is controversial whether similar mechanisms operate in humans. We found that human caspase-4, a member of caspase-1 subfamily that includes caspase-12, is localized to the ER membrane, and is cleaved when cells are treated with ER stress-inducing reagents, but not with other apoptotic reagents. Cleavage of caspase-4 is not affected by overexpression of Bcl-2, which prevents signal transduction on the mitochondria, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Furthermore, a reduction of caspase-4 expression by small interfering RNA decreases ER stress-induced apoptosis in some cell lines, but not other ER stress-independent apoptosis. Caspase-4 is also cleaved by administration of Abeta, and Abeta-induced apoptosis is reduced by small interfering RNAs to caspase-4. Thus, caspase-4 can function as an ER stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer's disease.