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

TY - JOUR

T1 - Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9.

AU - Gyrd-Hansen, Mads

AU - Farkas, Thomas

AU - Fehrenbacher, Nicole

AU - Bastholm, Lone

AU - Høyer-Hansen, Maria

AU - Elling, Folmer

AU - Wallach, David

AU - Flavell, Richard

AU - Kroemer, Guido

AU - Nylandsted, Jesper

AU - Jäättelä, Marja

N1 - Keywords: Animals; Apoptosis; Apoptotic Protease-Activating Factor 1; Caspase 8; Caspase 9; Cells, Cultured; Cycloheximide; Cytochromes c; Enzyme Activation; Fibroblasts; Lysosomes; Mice; Mice, Knockout; Mitochondria; Protein Synthesis Inhibitors; Tumor Necrosis Factor-alpha

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1128/MCB.00716-06

DO - 10.1128/MCB.00716-06

M3 - Journal article

C2 - 16966373

SN - 0270-7306

VL - 26

SP - 7880

EP - 7891

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

IS - 21

ER -