| First Author | Gyrd-Hansen M | Year | 2006 |
| Journal | Mol Cell Biol | Volume | 26 |
| Issue | 21 | Pages | 7880-91 |
| PubMed ID | 16966373 | Mgi Jnum | J:114641 |
| Mgi Id | MGI:3689655 | Doi | 10.1128/MCB.00716-06 |
| Citation | Gyrd-Hansen M, et al. (2006) Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. Mol Cell Biol 26(21):7880-91 |
| abstractText | 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. |
