Compartmentalization of TNF receptor 1 signaling:: Internalized TNF receptosomes as death signaling vesicles
Compartmentalization of TNF receptor 1 signaling:: Internalized TNF receptosomes as death signaling vesicles
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DOI：
10.1016/j.immuni.2004.08.017
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发表时间：
2004-09-01
期刊：
影响因子：
32.4
通讯作者：
Schütze, S
中科院分区：
文献类型：
--
作者：
Schneider-Brachert, W;Tchikov, V;Schütze, S
TNF-R1初始信号复合物募集的分子调控尚不明确。我们在这里证明，内化的TNF- r1 （TNF受体体）在几分钟内招募TRADD、FADD和caspase-8来建立“死亡诱导信号复合体”（DISC）。此外，我们发现了受体内吞作用所需的TNF-R1内化结构域（TRID），并提供证据证明TNF-R1内化、DISC形成和细胞凋亡是不可分割的事件。分析表达内化缺陷受体（TNF-R1 DeltaTRID）的细胞系发现，RIP-1和TRAF-2向TNF-R1的募集发生在质膜水平。相反，TRADD、FADD和caspase-8聚集以建立tnf - r1相关的DISC则严重依赖于受体内吞作用。此外，TNF受体体与反式高尔基囊泡的融合导致酸性鞘磷脂酶和组织蛋白酶d的激活。因此，TNF受体体通过将含有TNF- r1相关DISC的质膜来源的内吞囊泡区隔化，建立了不同的TNF信号通路。
The molecular regulation of the recruitment of initial signaling complexes at the TNF-R1 is poorly defined. We demonstrate here that within minutes internalized TNF-R1 (TNF receptosomes) recruits TRADD, FADD, and caspase-8 to establish the "death-inducing signaling complex" (DISC). In addition, we identified the TNF-R1 internalization domain (TRID) required for receptor endocytosis and provide evidence that TNF-R1 internalization, DISC formation, and apoptosis are inseparable events. Analyzing cell lines expressing an internalization-deficient receptor (TNF-R1 DeltaTRID) revealed that recruitment of RIP-1 and TRAF-2 to TNF-R1 occurred at the level of the plasma membrane. In contrast, aggregation of TRADD, FADD, and caspase-8 to establish the TNF-R1-associated DISC is critically dependent on receptor endocytosis. Furthermore, fusion of TNF receptosomes with trans-Golgi vesicles results in activation of acid sphingomyelinase and cathepsin D. Thus, TNF receptosomes establish the different TNF signaling pathways by compartmentalization of plasma membrane-derived endocytic vesicles harboring the TNF-R1-associated DISC.