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首页> 外文期刊>Molecular and Cellular Biology >Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death
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Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

机译：线粒体的新作用：激活诱导的T细胞死亡中的蛋白激酶Cθ依赖氧化信号细胞器。

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Reactive oxygen species (ROS) play a key role in regulation of activation-induced T-cell death (AICD) by induction of CD95L expression. However, the molecular source and the signaling steps necessary for ROS production are largely unknown. Here, we show that the proximal T-cell receptor-signaling machinery, including ZAP70 (zeta chain-associated protein kinase 70), LAT (linker of activated T cells), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa), PLCγ1 (phospholipase Cγ1), and PKCθ (protein kinase Cθ), are crucial for ROS production. PKCθ is translocated to the mitochondria. By using cells depleted of mitochondrial DNA, we identified the mitochondria as the source of activation-induced ROS. Inhibition of mitochondrial electron transport complex I assembly by small interfering RNA (siRNA)-mediated knockdown of the chaperone NDUFAF1 resulted in a block of ROS production. Complex I-derived ROS are converted into a hydrogen peroxide signal by the mitochondrial superoxide dismutase. This signal is essential for CD95L expression, as inhibition of complex I assembly by NDUFAF1-specific siRNA prevents AICD. Similar results were obtained when metformin, an antidiabetic drug and mild complex I inhibitor, was used. Thus, we demonstrate for the first time that PKCθ-dependent ROS generation by mitochondrial complex I is essential for AICD.
机译：活性氧（ROS）通过诱导CD95L表达而在激活诱导的T细胞死亡（AICD）的调节中起关键作用。但是，ROS产生所必需的分子来源和信号传导步骤尚不清楚。在这里，我们显示了近端T细胞受体信号转导机制，包括ZAP70（ζ链相关蛋白激酶70），LAT（活化T细胞的接头），SLP76（含SH2域的白细胞蛋白76 kDa），PLCγ1 （磷脂酶Cγ1）和PKCθ（蛋白激酶Cθ）对ROS的产生至关重要。 PKCθ易位至线粒体。通过使用耗尽线粒体DNA的细胞，我们将线粒体鉴定为激活诱导的ROS的来源。通过小分子干扰RNA（siRNA）介导的伴侣NDUFAF1的敲低抑制线粒体电子运输复合体I组装导致ROS生成受阻。线粒体超氧化物歧化酶将复合物I衍生的ROS转化为过氧化氢信号。该信号对于CD95L表达至关重要，因为NDUFAF1特异性siRNA抑制复合物I装配可防止AICD。当使用二甲双胍（一种抗糖尿病药和轻度复合物I抑制剂）获得相似的结果。因此，我们首次证明线粒体复合体I产生PKCθ依赖性ROS对于AICD是必不可少的。

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