Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis.
Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis.
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DOI：
10.1084/jem.20041685
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发表时间：
2005-07-18
期刊：
影响因子：
--
通讯作者：
Umehara H
中科院分区：
文献类型：
--
作者：
Miyaji M;Jin ZX;Yamaoka S;Amakawa R;Fukuhara S;Sato SB;Kobayashi T;Domae N;Mimori T;Bloom ET;Okazaki T;Umehara H
Fas受体（CD 95）的参与启动了导致细胞凋亡的多种信号传导途径，例如死亡诱导信号复合物（DISC）的形成、半胱天冬酶级联的激活以及脂质信使神经酰胺的产生。鞘磷脂（SM）是脂筏的主要成分，脂筏是增强膜受体信号传导效率的特化结构，并且是神经酰胺的主要来源。然而，SM在Fas介导的细胞凋亡中的功能尚未明确定义，因为尚未确定负责基因。在克隆了负责SM合成的基因SMS 1后，我们建立了转染了人Fas基因的SM转移酶缺陷型WR 19 L细胞（WR/Fas-SM（-））和通过转染SMS 1恢复了功能的细胞（WR/Fas-SMS 1）。我们发现，膜SM的表达增强Fas介导的细胞凋亡，通过增加DISC的形成，激活半胱氨酸天冬氨酸蛋白酶，有效的转运Fas到脂筏，和随后的Fas集群。此外，WR/Fas-SMS 1细胞，而不是WR/Fas-SM（-）细胞，表现出在Fas刺激下脂筏内神经酰胺产生的显著增加。这些数据表明，膜SM是重要的Fas聚集通过聚集的脂筏，导致Fas介导的凋亡。
Engagement of the Fas receptor (CD95) initiates multiple signaling pathways that lead to apoptosis, such as the formation of death-inducing signaling complex (DISC), activation of caspase cascades, and the generation of the lipid messenger, ceramide. Sphingomyelin (SM) is a major component of lipid rafts, which are specialized structures that enhance the efficiency of membrane receptor signaling and are a main source of ceramide. However, the functions of SM in Fas-mediated apoptosis have yet to be clearly defined, as the responsible genes have not been identified. After cloning a gene responsible for SM synthesis, SMS1, we established SM synthase–defective WR19L cells transfected with the human Fas gene (WR/Fas-SM(−)), and cells that have been functionally restored by transfection with SMS1 (WR/Fas-SMS1). We show that expression of membrane SM enhances Fas-mediated apoptosis through increasing DISC formation, activation of caspases, efficient translocation of Fas into lipid rafts, and subsequent Fas clustering. Furthermore, WR/Fas-SMS1 cells, but not WR/Fas-SM(−) cells, showed a considerable increase in ceramide generation within lipid rafts upon Fas stimulation. These data suggest that a membrane SM is important for Fas clustering through aggregation of lipid rafts, leading to Fas-mediated apoptosis.
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影响因子：
4.8
作者：
Cremesti, A;Paris, F;Kolesnick, R
通讯作者：
Kolesnick, R
影响因子：
4
作者：
Hetz, CA;Hunn, M;Quest, AFG
通讯作者：
Quest, AFG
影响因子：
4.8
作者：
Kamitani, T;Nguyen, HP;Yeh, ETH
通讯作者：
Yeh, ETH
DOI：
10.1073/pnas.96.26.14871
发表时间：
1999-12-21
影响因子：
11.1
作者：
Huang, DCS;Hahne, M;Strasser, A
通讯作者：
Strasser, A
影响因子：
3.6
作者：
Kondo, T;Suzuki, Y;Okazaki, T
通讯作者：
Okazaki, T