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Compartimentalization of TNF-receptor 1 signalling: acid sphingomyelinase is activated by Caspase-8 in internalized TNF-R1 receptosomes

In a recently identified novel TNF-induced apoptotic signaling pathway the generation of ceramide by acid sphingomyelinase (A-SMase) and the activation of the aspartic protease cathepsin D (CTSD) occur in the same endosomal compartment [1]. CTSD subsequently mediates cleavage of Bid leading to activation of caspase-9 and -3. Since activation of A-SMase is linked to the death domain of TNF-receptor 1 (TNF-R1) and since the death domain adapter proteins FADD and caspase-8 are recruited during internalization of TNF-R1 in endosomes (TNF-receptosomes) [2], we addressed the question, whether A-SMase can be activated directly by caspase-8 within this compartment. We here show by confocal laser scan microscopy and in immunomagnetically isolated TNF-receptosome preparations that the active form of caspase-8 colocalizes with A-SMase within TNF-receptosomes. Activation of caspase-8 correlates with cleavage of a 70/72 kDa pro-A-SMase molecule, paralleled by enhanced A-SMase activity, activation of CTSD as well as Bid-cleavage in isolated TNF-receptosomes. The functional link between caspase-8 activity and A-SMase stimulation is revealed by the lack of TNF-induced A-SMase activation in caspase-8 deficient Jurkat cells, which can be restored in vivo after retransfection of caspase-8 as well as in vitro by the addition of exogenous caspase-8 to lysates from caspase-8 deficient cells.


  1. Heinrich M, Neumeyer J, Jakob M, Hallas C, Tchikov V, Winoto-Morbach S, Wickel M, Schneider-Brachert W, Trauzold A, Hethke A, Schütze S: Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ. 2004, 11 (5): 550-563. 10.1038/sj.cdd.4401382.

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  2. Schneider-Brachert W, Tchikov V, Neumeyer J, Jakob M, Winoto-Morbach S, Held-Feindt J, Heinrich M, Merkel O, Ehrenschwender M, Adam D, Mentlein R, Kabelitz D, Schütze S: Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity. 2004, 21 (3): 415-428.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Edelmann, B., Bertsch, U., Hallas, C. et al. Compartimentalization of TNF-receptor 1 signalling: acid sphingomyelinase is activated by Caspase-8 in internalized TNF-R1 receptosomes. Cell Commun Signal 7 (Suppl 1), A13 (2009).

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