The extracellular glycosphingolipid-binding motif of Fas defines its internalization route, mode and outcome of signals upon activation by ligand
The extracellular glycosphingolipid-binding motif of Fas defines its internalization route, mode and outcome of signals upon activation by ligand
复制标题
DOI：
10.1038/cdd.2008.115
复制
发表时间：
2008-12-01
影响因子：
12.4
通讯作者：
Hueber, A-O
中科院分区：
文献类型：
--
作者：
Chakrabandhu, K.;Huault, S.;Hueber, A-O
选择性区隔化和内化已被证明是调节细胞表面受体的特定信号以适应细胞需求和条件的一种手段。在这里，我们提出了一个保守的细胞外糖鞘脂结合基序Fas作为其内化途径选择的调控元件之一，从而在配体结合时传递信号。这个基序是网格蛋白介导的Fas内化所必需的，它允许其细胞死亡信号的转导。基序功能的丧失驱动激活的受体转向另一种内化途径，该途径不依赖网格蛋白和胆固醇依赖性筏，但依赖于ezrin，从而在促进其非死亡功能的同时消除其细胞死亡信号。通过生化、生物物理和遗传方法，我们提出了一种基于蛋白质/脂质的机制，作为多功能Fas受体配体系统信号转导的多功能性的关键。
Selective compartmentalization and internalization have been shown as a means for regulating specific signals of cell surface receptors to correspond to cellular requirements and conditions. Here, we present a conserved extracellular glycosphingolipid-binding motif of Fas as one of the regulatory elements in the selection of its internalization route and consequently the signals transmitted upon ligand binding. This motif is required for clathrin-mediated internalization of Fas, which allows the transduction of its cell death signal. The loss of function of the motif drives the activated receptor to an alternative internalization route that is independent of clathrin and cholesterol-dependent rafts but dependent on ezrin, and thereby extinguishing its cell death signal while promoting its non-death functions. Through biochemical, biophysical, and genetic approaches, we present a protein/lipid-based mechanism as a key to the versatility of the signal transduction by the multifunctional Fas receptor-ligand system.