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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.

SUBMITTER: Gyrd-Hansen M 

PROVIDER: S-EPMC1636747 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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

Gyrd-Hansen Mads M   Farkas Thomas T   Fehrenbacher Nicole N   Bastholm Lone L   Høyer-Hansen Maria M   Elling Folmer F   Wallach David D   Flavell Richard R   Kroemer Guido G   Nylandsted Jesper J   Jäättelä Marja M  

Molecular and cellular biology 20060911 21


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 effect  ...[more]

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