A novel cytoplasmic domain of the p55 tumor necrosis factor receptor initiates the neutral sphingomyelinase pathway
A novel cytoplasmic domain of the p55 tumor necrosis factor receptor initiates the neutral sphingomyelinase pathway
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DOI：
10.1074/jbc.271.24.14617
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发表时间：
1996-06-14
影响因子：
4.8
通讯作者：
Kronke, M
中科院分区：
文献类型：
--
作者：
Adam, D;Wiegmann, K;Kronke, M
人 p55 肿瘤坏死因子 (TNF) 受体 (TR55) 启动至少两个独立的信号级联。酸性鞘磷脂酶 (A-SMase) 途径涉及磷脂酰胆碱特异性磷脂酶 C、内体 A-SMase，并通过诱导 NF-κ B 等转录因子控制多种 TNF 反应基因的表达。中性鞘磷脂酶 (N-SMase) 途径包括膜结合 N-SMase、脯氨酸定向蛋白激酶以及磷脂酶 A(2)并且对于 TNF 诱导的炎症反应至关重要。虽然诱导 A-SMase 的 TR55 结构域可能与死亡结构域相同，但假定的 N-SMase 激活结构域的确切位置和范围仍然未知。 TR55 缺失突变体的结构功能分析揭示了第 309-319 位的 11 个氨基酸的新区域，该区域对于 N-SMase 的激活是必要且充分的。 N-SMase 激活结构域与死亡结构域不同，不能诱导 A-SMase、NF-κ B 和细胞毒性。综上所述，我们的结果表明 TR55 的功能独立区域负责选择性启动 N-SMase 通路，该通路与重要的炎症信号级联反应耦合。
The human p55 tumor necrosis factor (TNF) receptor (TR55) initiates at least two independent signaling cascades. The acidic sphingomyelinase (A-SMase) pathway involves a phosphatidylcholine-specific phospholipase C, an endosomal A-SMase, and controls expression of multiple TNF-responsive genes through induction of transcription factors such as NF-kappa B. The neutral sphingomyelinase (N-SMase) pathway comprises a membrane-bound N-SMase, proline-directed protein kinases, as well as phospholipase A(2) and appears critical for the inflammatory responses induced by TNF. While the domain of TR55 that induces A-SMase is probably identical to the death domain, the exact location and extent of a putative N-SMase activation domain are still unknown. Structure-function analysis of TR55 deletion mutants revealed a novel region of 11 amino acids at position 309-319 that is both necessary and sufficient for activation of N-SMase. The N-SMase activation domain is distinct from the death domain and incapable of induction of A-SMase, NF-kappa B, and cytotoxicity. Taken together, our results suggest that a functionally independent region of TR55 is responsible for selectively initiating the N-SMase pathway that couples to an important inflammatory signaling cascade.