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

Mads Gyrd-Hansen; Thomas Farkas; Nicole Fehrenbacher; Lone Bastholm; Maria Høyer-Hansen; Folmer Elling; David Wallach; Richard Flavell; Guido Kroemer; Jesper Nylandsted; Marja Jäättelä

doi:10.1128/MCB.00716-06

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

Mads Gyrd-Hansen, Thomas Farkas, Nicole Fehrenbacher, Lone Bastholm, Maria Høyer-Hansen, Folmer Elling, David Wallach, Richard Flavell, Guido Kroemer, Jesper Nylandsted, Marja Jäättelä

87 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Molecular and Cellular Biology
Volume	26
Issue number	21
Pages (from-to)	7880-91
Number of pages	11
ISSN	0270-7306
DOIs	https://doi.org/10.1128/MCB.00716-06
Publication status	Published - 2006
Externally published	Yes

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@article{96dab9f0524911dd8d9f000ea68e967b,

title = "Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9.",

abstract = "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.",

author = "Mads Gyrd-Hansen and Thomas Farkas and Nicole Fehrenbacher and Lone Bastholm and Maria H{\o}yer-Hansen and Folmer Elling and David Wallach and Richard Flavell and Guido Kroemer and Jesper Nylandsted and Marja J{\"a}{\"a}ttel{\"a}",

note = "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",

year = "2006",

doi = "10.1128/MCB.00716-06",

language = "English",

volume = "26",

pages = "7880--91",

journal = "Molecular and Cellular Biology",

issn = "0270-7306",

publisher = "American Society for Microbiology",

number = "21",

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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 -

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

Abstract

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