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Compartimentalization of TNF-receptor 1 signalling: acid sphingomyelinase is activated by Caspase-8 in internalized TNF-R1 receptosomes
Cell Communication and Signaling volume 7, Article number: A13 (2009)
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 . 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) , 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.
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.
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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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, A13 (2009) doi:10.1186/1478-811X-7-S1-A13
- Confocal Laser
- Adapter Protein
- Jurkat Cell
- Apoptotic Signaling