Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9
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Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. / Gyrd-Hansen, M.; Farkas, T.; Fehrenbacher, N.; Bastholm, L.; Høyer-Hansen, M.; Elling, F.; Wallach, D.; Flavell, R.; Kroemer, G.; Nylandsted, J.; Jäättelä, M.
In: Molecular and Cellular Biology, Vol. 26, No. 21, 2006, p. 7880-7891.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9
AU - Gyrd-Hansen, M.
AU - Farkas, T.
AU - Fehrenbacher, N.
AU - Bastholm, L.
AU - Høyer-Hansen, M.
AU - Elling, F.
AU - Wallach, D.
AU - Flavell, R.
AU - Kroemer, G.
AU - Nylandsted, J.
AU - Jäättelä, M.
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.
UR - https://www.tandfonline.com/doi/full/10.1128/MCB.00563-17
U2 - 10.1128/MCB.00716-06
DO - 10.1128/MCB.00716-06
M3 - Journal article
VL - 26
SP - 7880
EP - 7891
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 21
ER -
ID: 329246907