An essential role for membrane rafts in the initiation of Fas/CD95-triggered cell death in mouse thymocytes
An essential role for membrane rafts in the initiation of Fas/CD95-triggered cell death in mouse thymocytes
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DOI：
10.1093/embo-reports/kvf022
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发表时间：
2002-02-01
期刊：
影响因子：
7.7
通讯作者：
He, HT
中科院分区：
文献类型：
--
作者：
Hueber, AO;Bernard, AM;He, HT
Fas是肿瘤坏死因子受体家族的成员，在与其配体或激动性抗体连接后可以触发信号级联反应，导致淋巴细胞和其他细胞类型的细胞死亡。这种信号级联通过形成膜死亡诱导信号复合物（DISC）而启动，所述膜死亡诱导信号复合物包括Fas、Fas相关死亡结构域蛋白（FADD）和半胱天冬酶-8。我们在这里报告，相当一部分的Fas组成性分配到鞘脂和胆固醇丰富的膜筏小鼠胸腺细胞以及L12.10-Fas T细胞，Fas连接促进快速和特异性的招聘FADD和caspase-8的筏。通过胆固醇消耗的筏破坏消除Fas触发的FADD和半胱天冬酶-8向膜的募集、DISC形成和细胞死亡。两者合计，我们的研究结果提供了第一个示范的一个重要作用的膜筏启动Fas介导的细胞死亡信号。
Fas, a member of the tumor necrosis factor receptor family, can upon ligation by its ligand or agonistic antibodies trigger signaling cascades leading to cell death in lymphocytes and other cell types. Such signaling cascades are initiated through the formation of a membrane death-inducing signaling complex (DISC) that includes Fas, the Fas-associated death domain protein (FADD) and caspase-8. We report here that a considerable fraction of Fas is constitutively partitioned into sphingolipid- and cholesterol-rich membrane rafts in mouse thymocytes as well as the L12.10-Fas T cells, and Fas ligation promotes a rapid and specific recruitment of FADD and caspase-8 to the rafts. Raft disruption by cholesterol depletion abolishes Fas-triggered recruitment of FADD and caspase-8 to the membrane, DISC formation and cell death. Taken together, our results provide the first demonstration for an essential role of membrane rafts in the initiation of Fas-mediated cell death signaling.