TNF-receptor I defective in internalization allows for cell death through activation of neutral sphingomyelinase

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• 作者：Jens Neumeyer ; Cora Hallas ; Oliver Merkel ; Supandi Winoto-Morbach ; Marten Jakob ; Lutz Thon ; Dieter Adam ; Wulf Schneider-Brachert and Stefan Schü ; tze
• 关键词：Caspase ; Cathepsin D ; Sphingomyelinase ; TNF-RI ; Apoptosis ; DISC
• 刊名：Experimental Cell Research
• 出版年：2006
• 出版时间：1 July 2006
• 年：2006
• 卷：312
• 期：11
• 页码：2142-2153
• 全文大小：948 K

文摘

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 ΔTRID, 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 ΔTRID 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 ΔTRID 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.