ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1

• Published in: Journal of cell science Vol. 119; no. 19; pp. 3958 - 3966
• Main Authors: Shiraishi, Hiroshi, Okamoto, Hideaki, Yoshimura, Akihiko, Yoshida, Hiroki
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Limited 01.10.2006
• Subjects: Animals; apoptosis; Apoptosis - physiology; Apoptotic Protease-Activating Factor 1 - genetics; Apoptotic Protease-Activating Factor 1 - physiology; bcl-X Protein - physiology; Caspase 12 - metabolism; Caspase 3 - metabolism; Cell Survival; Cells, Cultured; cysteine proteinases; cytochrome c; Cytochromes c - metabolism; Cytoprotection; Embryo, Mammalian - cytology; endoplasmic reticulum; Endoplasmic Reticulum - physiology; fibroblasts; kidneys; Mice; mitochondria; Mitochondria - physiology; protein transport; Stress, Physiological - metabolism
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.03160

Accumulation of unfolded proteins induces endoplasmic reticulum (ER) stress. Excessive and prolonged stresses lead cells to apoptosis. However, the precise molecular mechanisms of ER stress-induced apoptosis have not been fully elucidated. We investigated the involvement of the apoptosome in ER stress-induced cell death pathway using mouse embryonic fibroblasts (MEFs) and mice deficient for Apaf-1. Apaf-1-deficient MEFs showed more resistance to ER stress-inducing reagents as compared with wild type cells. Despite comparable induction of ER stress in both wild type and Apaf-1-deficient cells, activation of caspase-3 was only observed in wild type, but not Apaf-1-deficient, MEFs. Under ER stress conditions, BAX translocated to mitochondria and cytochrome c was released from mitochondria. We also demonstrated that caspase-12 was processed downstream of Apaf-1 and caspase-3, and neither overexpression nor knockdown of caspase-12 affected susceptibility of the cells to ER stress-induced cell death. Furthermore, in the kidneys of Apaf-1-deficient mice, apoptosis induced by in vivo administration of tunicamycin was remarkably suppressed as compared with wild type mice. These data collectively demonstrated that Apaf-1 and the mitochondrial pathway of apoptosis play significant roles in ER stress-induced apoptosis.