Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9.

Journal article

The apoptosome, a heptameric complex of Apaf-1, cytochrome c, and caspase-9, has been considered indispensable for the activation of caspase-9 during apoptosis. By using a large panel of genetically modified murine embryonic fibroblasts, we show here that, in response to tumor necrosis factor (TNF), caspase-8 cleaves and activates caspase-9 in an apoptosome-independent manner. Interestingly, caspase-8-cleaved caspase-9 induced lysosomal membrane permeabilization but failed to activate the effector caspases whereas apoptosome-dependent activation of caspase-9 could trigger both events. Consistent with the ability of TNF to activate the intrinsic apoptosis pathway and the caspase-9-dependent lysosomal cell death pathway in parallel, their individual inhibition conferred only a modest delay in TNF-induced cell death whereas simultaneous inhibition of both pathways was required to achieve protection comparable to that observed in caspase-9-deficient cells. Taken together, the findings indicate that caspase-9 plays a dual role in cell death signaling, as an activator of effector caspases and lysosomal membrane permeabilization.

Authors: Gyrd-Hansen, M; Farkas, T; Fehrenbacher, N; Bastholm, L; Høyer-Hansen, M

• Journal: Molecular and cellular biology
• Volume: 26
• Issue: 21
• Pages: 7880-7891
• Publication date: 2006-11-01
• DOI: 10.1128/mcb.00716-06
• EISSN: 1098-5549
• ISSN: 0270-7306
• Language: English
• Keywords: Mitochondria; Apoptotic Protease-Activating Factor 1; Fibroblasts; Tumor Necrosis Factor-alpha; Caspase 9; Lysosomes; Cytochromes c; Cells, Cultured; Mice; Caspase 8; Animals; Apoptosis; Mice, Knockout; Cycloheximide; Protein Synthesis Inhibitors; Enzyme Activation