TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis
TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis
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DOI：
10.1038/sj.onc.1209568
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发表时间：
2006-09-14
期刊：
影响因子：
8
通讯作者：
Gulbins, E.
中科院分区：
文献类型：
--
作者：
Dumitru, C. A.;Gulbins, E.
我们以前已经表明，激活的酸性鞘磷脂酶（ASM），神经酰胺的释放和神经酰胺富集的膜结构域的形成是由CD 95诱导细胞凋亡的核心。在这里，我们证明，肿瘤坏死因子相关凋亡诱导配体（TRAIL）和CD 95激活ASM通过氧化还原机制，导致神经酰胺的释放和形成富含神经酰胺的膜平台。富含神经酰胺的膜平台用于在刺激时聚集DR 5。抗氧化剂阻止TRAIL介导的ASM刺激、神经酰胺的释放、富含神经酰胺的膜平台的形成和TRAIL诱导的细胞凋亡。此外，ASM缺陷的脾细胞不能聚集DR 5在神经酰胺富集的膜结构域后，TRAIL刺激和抵抗TRAIL诱导的细胞凋亡，通过添加天然C-16-神经酰胺恢复的事件。剂量-反应分析表明，神经酰胺富集的膜平台极大地使肿瘤细胞对TRAIL诱导的细胞凋亡敏感。我们的数据表明，在生理条件下，TRAIL-DR 5复合物的信号传导需要富含神经酰胺的膜平台。
We have previously shown that activation of the acid sphingomyelinase (ASM), the release of ceramide and the formation of ceramide-enriched membrane domains are central for the induction of apoptosis by CD95. Here, we demonstrate that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95 activate the ASM via a redox mechanism resulting in release of ceramide and formation of ceramide-enriched membrane platforms. Ceramide-enriched membrane platforms serve to cluster DR5 upon stimulation. Antioxidants prevent TRAIL-mediated stimulation of ASM, the release of ceramide, the formation of ceramide-enriched membrane platforms and the induction of apoptosis by TRAIL. Further, ASM-deficient splenocytes fail to cluster DR5 in ceramide-enriched membrane domains upon TRAIL stimulation and resist TRAIL-induced apoptosis, events that were restored by addition of natural C-16-ceramide. A dose-response analysis indicates that ceramide-enriched membrane platforms greatly sensitized tumor cells to TRAIL-induced apoptosis. Our data indicate that ceramide-enriched membrane platforms are required for the signaling of TRAIL-DR5 complexes under physiological conditions.