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Mol. Cell. Biol. 26 (21): 7880-7891

Copyright © 2006 by the American Society for Microbiology. All rights reserved.

Apoptosome-Independent Activation of the Lysosomal Cell Death Pathway by Caspase-9{triangledown} ,{dagger}

Mads Gyrd-Hansen,1,2,{ddagger} Thomas Farkas,1 Nicole Fehrenbacher,1 Lone Bastholm,2 Maria Høyer-Hansen,1 Folmer Elling,2 David Wallach,3 Richard Flavell,4 Guido Kroemer,5 Jesper Nylandsted,1, and Marja Jäättelä1*

Apoptosis Department and Centre for Genotoxic Stress, Institute for Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark,1 Institute of Molecular Pathology, University of Copenhagen, DK-2100 Copenhagen, Denmark,2 Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel,3 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520,4 Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, F-94805 Villejuif, France5

Received for publication 26 April 2006. Revision received 26 May 2006. Accepted for publication 15 August 2006.

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.

* Corresponding author. Mailing address: Apoptosis Department and Centre for Genotoxic Stress, Institute for Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. Phone: 45-35257318. Fax: 45-35257721. E-mail: mj{at}

{triangledown} Published ahead of print on 11 September 2006.

{dagger} Supplemental material for this article may be found at

{ddagger} Present address: The Breakthrough Toby Robins Breast Cancer Research Centre at The Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, United Kingdom.

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