Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9.
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),...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2006
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| _version_ | 1826262640842768384 |
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| author | Gyrd-Hansen, M Farkas, T Fehrenbacher, N Bastholm, L Høyer-Hansen, M Elling, F Wallach, D Flavell, R Kroemer, G Nylandsted, J Jäättelä, M |
| author_facet | Gyrd-Hansen, M Farkas, T Fehrenbacher, N Bastholm, L Høyer-Hansen, M Elling, F Wallach, D Flavell, R Kroemer, G Nylandsted, J Jäättelä, M |
| author_sort | Gyrd-Hansen, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T19:39:15Z |
| format | Journal article |
| id | oxford-uuid:2016f36b-951e-40a4-b962-e156f4c1c0f5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:39:15Z |
| publishDate | 2006 |
| record_format | dspace |
| spelling | oxford-uuid:2016f36b-951e-40a4-b962-e156f4c1c0f52022-03-26T11:25:41ZApoptosome-independent activation of the lysosomal cell death pathway by caspase-9.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2016f36b-951e-40a4-b962-e156f4c1c0f5EnglishSymplectic Elements at Oxford2006Gyrd-Hansen, MFarkas, TFehrenbacher, NBastholm, LHøyer-Hansen, MElling, FWallach, DFlavell, RKroemer, GNylandsted, JJäättelä, MThe 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. |
| spellingShingle | Gyrd-Hansen, M Farkas, T Fehrenbacher, N Bastholm, L Høyer-Hansen, M Elling, F Wallach, D Flavell, R Kroemer, G Nylandsted, J Jäättelä, M Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. |
| title | Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. |
| title_full | Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. |
| title_fullStr | Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. |
| title_full_unstemmed | Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. |
| title_short | Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. |
| title_sort | apoptosome independent activation of the lysosomal cell death pathway by caspase 9 |
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