ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1.
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.
Shiraishi
Hiroshi
H
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Japan.
Okamoto
Hideaki
H
Yoshimura
Akihiko
A
Yoshida
Hiroki
H
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000502:physiology*; D053454:Caspase 12 / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection; D004622:Embryo, Mammalian / Q000166:cytology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D013312:Stress, Physiological / Q000378:metabolism*; D051020:bcl-X Protein / Q000502:physiology
C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; C494812:Bcl2l1 protein, mouse; D051020:bcl-X Protein; D045304:Cytochromes c; D053454:Caspase 12; D053148:Caspase 3