Protease activity of procaspase-8 is essential for cell survival by inhibiting both apoptotic and nonapoptotic cell death dependent on receptor-interacting protein kinase 1 (RIP1) and RIP3.
Caspase-8 has an important role as an initiator caspase during death receptor-mediated apoptosis. Moreover, it has been reported to contribute to the regulation of cell fate in various types of cells including T-cells. In this report, we show that caspase-8 has an essential role in cell survival in mouse T-lymphoma-derived L5178Y cells. The knockdown of caspase-8 expression decreased the growth rate and increased cell death, both of which were induced by the absence of protease activity of procaspase-8. The cell death was associated with reactive oxygen species (ROS) accumulation, caspase activation, and autophagosome formation. The cell death was inhibited completely by treatment with ROS scavengers, but only partly by treatment with caspase inhibitors, expression of Bcl-xL, and knockdown of caspase-3 or Atg-7 which completely inhibits apoptosis or autophagosome formation, respectively, indicating that apoptosis and autophagy-associated cell death are induced simultaneously by the knockdown of caspase-8 expression. Further analysis indicated that RIP1 and RIP3 regulate this multiple cell death, because the cell death as well as ROS production was completely inhibited by not only treatment with the RIP1 inhibitor necrostatin-1, but also by knockdown of RIP3. Thus, in the absence of protease activity of procaspase-8, RIP1 and RIP3 simultaneously induce not only nonapoptotic cell death conceivably including autophagic cell death and necroptosis but also apoptosis through ROS production in mouse T-lymphoma cells.
Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
Mina
M
Kikuchi
Shunsuke
S
Kuroki
Mitsuhiro
M
Kayama
Shota
S
Sakaguchi
Kyung-Kwon
KK
Lee
Shin
S
Yonehara
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D053181:Caspase 8 / Q000737:chemistry* / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D016399:Lymphoma, T-Cell / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry*; D010447:Peptide Hydrolases / Q000737:chemistry*; D016601:RNA-Binding Proteins / Q000737:chemistry*; D017382:Reactive Oxygen Species; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000737:chemistry*; D013601:T-Lymphocytes / Q000378:metabolism
C119724:AGFG1 protein, human; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D010447:Peptide Hydrolases; D053181:Caspase 8