The 55-kDa tumor necrosis factor receptor induces clustering of mitochondria through its membrane-proximal region
The 55-kDa tumor necrosis factor receptor induces clustering of mitochondria through its membrane-proximal region
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DOI：
10.1074/jbc.273.16.9673
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发表时间：
1998-04-17
影响因子：
4.8
通讯作者：
Grooten, J
中科院分区：
文献类型：
--
作者：
De Vos, K;Goossens, V;Grooten, J
细胞因子肿瘤坏死因子（TNF）激活多种信号分子，导致基因表达、分化和/或细胞死亡。在这里，我们报告了一个新的功能诱导的TNF，即易位的线粒体从分散的分布到核周簇。线粒体易位与敏感性的细胞死亡诱导活性的TNF和介导的55 kDa的TNF受体（TNF-R55），但不是由Fas，表明信号转导途径需要一个TNF-RBS特异性，但死亡结构域独立的信号。事实上，使用表达突变型TNF-R55的L929细胞，我们表明TNF-R55的近膜区域对于线粒体易位的信号传导是必需的。在没有易位的情况下，细胞死亡反应明显延迟，这表明对细胞死亡的协同作用。线粒体的易位虽然依赖于微管，但并不受微管的影响，而是由运动蛋白驱动蛋白的TNF-非依赖性免疫抑制作用诱导的。此外，针对驱动蛋白尾部结构域的抗体的免疫抑制作用与TNF诱导的细胞死亡协同作用。基于这种功能模拟，我们提出，TNF-R55膜近端区域依赖性信号阻碍了与细胞因子相关的驱动蛋白，导致与TNF-R55死亡结构域诱导的细胞毒性反应的合作，并导致观察到的线粒体聚集。
The cytokine tumor necrosis factor (TNF) activates diverse signaling molecules resulting in gene expression, differentiation, and/or cell death. Here we report a novel feature induced by TNF, namely translocation of mitochondria from a dispersed distribution to a perinuclear cluster. Mitochondrial translocation correlated with sensitivity to the cell death-inducing activity of TNF and was mediated by the 55-kDa TNF receptor (TNF-R55), but not by Fas, indicating that the signaling pathway requires a TNF-RBS-specific but death domain-independent signal. Indeed, using L929 cells that express mutant TNF-R55, we showed that the membrane-proximal region of TNF-R55 was essential for signaling to mitochondrial translocation. In the absence of translocation, the cell death response was markedly delayed, pointing to a cooperative effect on cell death, Translocation of mitochondria, although dependent on the microtubules, was not imposed by the latter and was equally induced by TNF-independent immunoinhibition of the motor protein kinesin, Additionally, immunoinhibition with antibody directed against the tail domain of kinesin synergized with TNF-induced cell death. Based on this functional mimicry, we propose that a TNF-R55 membrane-proximal region-dependent signal impedes mitochondria-associated kinesin, resulting in cooperation with the TNF-R55 death domain-induced cytotoxic response and causing the observed clustering of mitochondria.