Adam D, Wiegmann K, Adam-Klages S, Ruff A, Krönke M
Institut für Immunologie, Christian-Albrechts-Universität Kiel, 24105 Kiel, Germany.
J Biol Chem. 1996 Jun 14;271(24):14617-22. doi: 10.1074/jbc.271.24.14617.
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-kappaB. The neutral sphingomyelinase (N-SMase) pathway comprises a membrane-bound N-SMase, proline-directed protein kinases, as well as phospholipase A2 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-kappaB, 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.
人p55肿瘤坏死因子（TNF）受体（TR55）启动至少两条独立的信号级联反应。酸性鞘磷脂酶（A-SMase）途径涉及一种磷脂酰胆碱特异性磷脂酶C、一种内体A-SMase，并通过诱导转录因子如NF-κB来控制多个TNF反应性基因的表达。中性鞘磷脂酶（N-SMase）途径包括一种膜结合N-SMase、脯氨酸定向蛋白激酶以及磷脂酶A2，对于TNF诱导的炎症反应似乎至关重要。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不清楚。TR55缺失突变体的结构-功能分析揭示了位于309-319位的一个11个氨基酸的新区域，该区域对于激活N-SMase既必要又充分。N-SMase激活结构域与死亡结构域不同，不能诱导A-SMase、NF-κB和细胞毒性。综上所述，我们的结果表明，TR55的一个功能独立区域负责选择性启动与重要炎症信号级联反应相关的N-SMase途径。
