Caspase-8 Mediates Mitochondrial Release of Pro-apoptotic Proteins in a Manner Independent of Its Proteolytic Activity in Apoptosis Induced by the Protein Synthesis Inhibitor Acetoxycycloheximide in Human Leukemia Jurkat Cells Export

@article{citeulike:4090470, abstract = {The cysteine protease caspase-8 plays an essential role in apoptosis induced by death receptors. The protein synthesis inhibitor acetoxycycloheximide (Ac-CHX) has been previously shown to induce rapid apoptosis mediated by the release of cytochrome c in human leukemia Jurkat cells. In this study, the novel molecular mechanism that links caspase-8 to the mitochondrial release of pro-apoptotic proteins has been identified. Jurkat cells deficient in caspase-8 were more resistant to Ac-CHX than wild-type Jurkat cells and manifested decreased apoptosis induction and caspase activation as well as inefficient release of cytochrome c, Smac/DIABLO, and AIF into the cytosol. In contrast to Fas ligand stimulation, the general caspase inhibitor barely prevented the mitochondrial release of these pro-apoptotic proteins in Ac-CHX-treated cells, suggesting that caspase-8 activity is dispensable for triggering the mitochondrial pathway in Ac-CHX-induced apoptosis. Consistent with this notion, caspase-8-deficient Jurkat cells reconstituted with catalytically inactive caspase-8 became sensitive to Ac-CHX and exhibited apoptosis, caspase activation, the liberation of pro-apoptotic proteins into the cytosol, and Bak conformational change as efficiently as wild-type Jurkat cells. Unlike caspase-3, -6, -7, and -9, a small but significant portion of caspase-8 was found to localize in mitochondria before and after exposure to Ac-CHX. These results clearly demonstrate that caspase-8 is able to mediate the mitochondrial release of pro-apoptotic proteins in a manner independent of its proteolytic activity in Ac-CHX-induced apoptosis. 10.1074/jbc.M808523200}, author = {Kadohara, Kimiko and Nagumo, Michiko and Asami, Shun and Tsukumo, Yoshinori and Sugimoto, Hikaru and Igarashi, Masayuki and Nagai, Kazuo and Kataoka, Takao}, citeulike-article-id = {4090470}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M808523200}, citeulike-linkout-1 = {http://www.jbc.org/cgi/content/abstract/284/9/5478?rss=1}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19112105}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19112105}, day = {27}, doi = {10.1074/jbc.M808523200}, journal = {J. Biol. Chem.}, keywords = {apoptosis, caspase-8, independent, kadoh09pdf, midtochondra, proteolysis}, month = {February}, number = {9}, pages = {5478--5487}, posted-at = {2009-02-24 00:03:56}, priority = {2}, title = {Caspase-8 Mediates Mitochondrial Release of Pro-apoptotic Proteins in a Manner Independent of Its Proteolytic Activity in Apoptosis Induced by the Protein Synthesis Inhibitor Acetoxycycloheximide in Human Leukemia Jurkat Cells}, url = {http://dx.doi.org/10.1074/jbc.M808523200}, volume = {284}, year = {2009} }

TY - JOUR ID - citeulike:4090470 L3 - citeulike-article-id:4090470 N2 - The cysteine protease caspase-8 plays an essential role in apoptosis induced by death receptors. The protein synthesis inhibitor acetoxycycloheximide (Ac-CHX) has been previously shown to induce rapid apoptosis mediated by the release of cytochrome c in human leukemia Jurkat cells. In this study, the novel molecular mechanism that links caspase-8 to the mitochondrial release of pro-apoptotic proteins has been identified. Jurkat cells deficient in caspase-8 were more resistant to Ac-CHX than wild-type Jurkat cells and manifested decreased apoptosis induction and caspase activation as well as inefficient release of cytochrome c, Smac/DIABLO, and AIF into the cytosol. In contrast to Fas ligand stimulation, the general caspase inhibitor barely prevented the mitochondrial release of these pro-apoptotic proteins in Ac-CHX-treated cells, suggesting that caspase-8 activity is dispensable for triggering the mitochondrial pathway in Ac-CHX-induced apoptosis. Consistent with this notion, caspase-8-deficient Jurkat cells reconstituted with catalytically inactive caspase-8 became sensitive to Ac-CHX and exhibited apoptosis, caspase activation, the liberation of pro-apoptotic proteins into the cytosol, and Bak conformational change as efficiently as wild-type Jurkat cells. Unlike caspase-3, -6, -7, and -9, a small but significant portion of caspase-8 was found to localize in mitochondria before and after exposure to Ac-CHX. These results clearly demonstrate that caspase-8 is able to mediate the mitochondrial release of pro-apoptotic proteins in a manner independent of its proteolytic activity in Ac-CHX-induced apoptosis. 10.1074/jbc.M808523200 IS - 9 JF - J. Biol. Chem. EP - 5487 TI - Caspase-8 Mediates Mitochondrial Release of Pro-apoptotic Proteins in a Manner Independent of Its Proteolytic Activity in Apoptosis Induced by the Protein Synthesis Inhibitor Acetoxycycloheximide in Human Leukemia Jurkat Cells VL - 284 SP - 5478 KW - apoptosis KW - caspase-8 KW - independent KW - kadoh09pdf KW - midtochondra KW - proteolysis AU - Kadohara, Kimiko AU - Nagumo, Michiko AU - Asami, Shun AU - Tsukumo, Yoshinori AU - Sugimoto, Hikaru AU - Igarashi, Masayuki AU - Nagai, Kazuo AU - Kataoka, Takao PY - 2009/02/27/ UR - http://dx.doi.org/10.1074/jbc.M808523200 ER -