TNF-receptor I defective in internalization allows for cell death through activation of neutral sphingomyelinase |
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Authors: | Neumeyer Jens Hallas Cora Merkel Oliver Winoto-Morbach Supandi Jakob Marten Thon Lutz Adam Dieter Schneider-Brachert Wulf Schütze Stefan |
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Institution: | Institute of Immunology, University Hospital of Schleswig-Holstein Campus Kiel, Michaelisstr. 5, D-24105 Kiel, Germany. |
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Abstract: | The cytoplasmic tail of the tumor necrosis factor receptor I (TNF-RI) contains several functionally distinct domains involved in apoptotic signaling. Mutants of TNF-RI carrying deletions of the death domain (DD), internalization domain (TRID), and neutral sphingomyelinase domain (NSD), respectively, retransfected in cells devoid of TNF-RI and TNF-RII, constituted distinct tools to evaluate the specific role of each domain in downstream apoptotic signaling events. Deletion of DD abolishes activation of caspase-3 and -9 and apoptosis following treatment with TNF because of blocked assembly of the DISC. Nevertheless, TNF-RI DeltaTRID, though lacking a DISC, still allows for residual activation of caspase-3 followed by cell death, although caspase-9 activation was not detected. This activity of caspase-3 is probably due to activation of neutral sphingomyelinase (N-SMase). Increased activity of this enzyme was detected in cells expressing TNF-RI DeltaTRID following treatment with TNF, but not in any other cell line investigated. N-SMase is activated by factor associated with N-SMase (FAN). Because TNF-RI DeltaTRID is retained at the cell surface, FAN may interact with the mutated receptor for a prolonged amount of time, thereby overactivating N-SMase. Double deletion of TRID and NSD abolished caspase-3 activation and apoptosis, confirming this hypothesis. |
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Keywords: | Caspase Cathepsin D Sphingomyelinase TNF-RI Apoptosis DISC |
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