Diacylglycerol kinase α regulates the secretion of lethal exosomes bearing Fas ligand during activation-induced cell death of T lymphocytes
Diacylglycerol kinase α regulates the secretion of lethal exosomes bearing Fas ligand during activation-induced cell death of T lymphocytes
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DOI：
10.1074/jbc.m501112200
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发表时间：
2005-08-05
影响因子：
4.8
通讯作者：
Izquierdo, M
中科院分区：
文献类型：
--
作者：
Alonso, R;Rodríguez, MC;Izquierdo, M
Fas 配体 (FasL) 介导免疫系统中的细胞凋亡和炎症反应。 FasL 的功能很大程度上取决于 FasL 的不同形式；缺乏跨膜和胞质结构域的可溶性 Fas 配体是细胞凋亡的不良介质，而全长膜相关 FasL (mFasL) 则具有促细胞凋亡作用。 mFasL 可以通过携带 mFasL 的外泌体的分泌从 T 淋巴细胞中释放。外泌体中的 mFasL 保留了其触发 Fas 依赖性细胞凋亡的活性，提供了一种替代的细胞死亡机制，该机制不一定意味着细胞与细胞之间的接触。二酰甘油激酶 α (DGK α) 是一种二酰甘油 (DAG) 消耗酶，参与减弱质膜引发的 DAG 衍生反应，从而导致 T 淋巴细胞活化。在这里，我们研究了 DGK α 对 T 细胞系和原代 T 淋巴细胞激活诱导的细胞死亡的作用。 DGK α 的抑制会增加带有 mFas 配体的致命外泌体的分泌以及随后的细胞凋亡。相反，DGK α途径的过度激活会抑制外泌体的分泌和随后的细胞凋亡。发现 DGK α 与跨高尔基体网络和晚期内体区室相关。我们的结果支持这样的假设，即DGK α对细胞凋亡的影响是通过胞吐途径调节致死性外泌体的释放而发生的，并指出DGK α对不同DAG池（质膜和高尔基膜）的空间编排对于控制细胞活化以及调节致死性外泌体的分泌至关重要，从而控制细胞死亡。
Fas ligand ( FasL) mediates both apoptotic and inflammatory responses in the immune system. FasL function critically depends on the different forms of FasL; soluble Fas ligand lacking the transmembrane and cytoplasmic domains is a poor mediator of apoptosis, whereas full-length, membrane-associated FasL ( mFasL) is pro-apoptotic. mFasL can be released from T lymphocytes, via the secretion of mFasL-bearing exosomes. mFasL in exosomes retains its activity in triggering Fas-dependent apoptosis, providing an alternative mechanism of cell death that does not necessarily imply cell-to-cell contact. Diacylglycerol kinase alpha ( DGK alpha), a diacylglycerol ( DAG)-consuming enzyme, is involved in the attenuation of DAG-derived responses initiated at the plasma membrane that lead to T lymphocyte activation. Here we studied the role of DGK alpha on activation-induced cell death on a T cell line and primary T lymphoblasts. The inhibition of DGK alpha increases the secretion of lethal exosomes bearing mFas ligand and subsequent apoptosis. On the contrary, the overactivation of the DGK alpha pathway inhibits exosome secretion and subsequent apoptosis. DGK alpha was found associated with the trans-Golgi network and late endosomal compartments. Our results support the hypothesis that the DGK alpha effect on apoptosis occurs via the regulation of the release of lethal exosomes by the exocytic pathway, and point out that the spatial orchestration of the different pools of DAG ( plasma membrane and Golgi membranes) by DGK alpha is crucial for the control of cell activation and also for the regulation of the secretion of lethal exosomes, which in turn controls cell death.