Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death.
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.
Hitomi
Junichi
J
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Katayama
Taiichi
T
Eguchi
Yutaka
Y
Kudo
Takashi
T
Taniguchi
Manabu
M
Koyama
Yoshihisa
Y
Manabe
Takayuki
T
Yamagishi
Satoru
S
Bando
Yoshio
Y
Imaizumi
Kazunori
K
Tsujimoto
Yoshihide
Y
Tohyama
Masaya
M
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D015536:Down-Regulation / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007425:Intracellular Membranes / Q000201:enzymology; D008565:Membrane Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology
D016229:Amyloid beta-Peptides; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C018551:glucose-regulated proteins; C093516:CASP4 protein, human; D020169:Caspases; D053471:Caspases, Initiator