Prohibitin 1 modulates mitochondrial function of Stat3.
Prohibitin 1 modulates mitochondrial function of Stat3.
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DOI：
10.1016/j.cellsig.2014.06.006
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发表时间：
2014-10
影响因子：
4.8
通讯作者：
Theiss AL
中科院分区：
文献类型：
--
作者：
Han J;Yu C;Souza RF;Theiss AL
肠上皮细胞线粒体功能障碍(IEC)被认为是炎症性肠病(IBD)发病的先兆。Prohibitin 1(PHB)是一种具有最佳电子传递链(ETC)活性所需的线粒体蛋白，在活动期和非活动期IBD的粘膜活检组织中表达减少。除了作为转录因子的活性外，信号转导和转录激活因子3(STAT3)还存在于细胞的线粒体中，S727的磷酸化是最佳ETC活性所必需的，并对应激诱导的线粒体功能障碍具有保护作用。在这里，我们发现PHB的过度表达对肿瘤坏死因子α诱导的培养内皮细胞线粒体应激和凋亡具有保护作用，肿瘤坏死因子是一种参与IBD发病机制的促炎细胞因子。PS727-STAT3的显性负性表达消除了PHB对肿瘤坏死因子α诱导的线粒体应激和凋亡的保护作用。PHB与pS727-STAT3在培养的IECs的线粒体和野生型小鼠的结肠上皮细胞中相互作用。我们的数据表明，PHB具有依赖pS727-STAT3的保护作用，以防止IECS中的线粒体功能障碍。IBD期间PHB水平降低可能是促进肠上皮线粒体功能障碍的潜在因素。
Mitochondrial dysfunction in intestinal epithelial cells (IEC) is thought to precede the onset of inflammatory bowel diseases (IBD). Expression of Prohibitin 1 (PHB), a mitochondrial protein required for optimal electron transport chain (ETC) activity, is decreased in mucosal biopsies during active and inactive IBD. In addition to its activities as a transcription factor, Signal Transducer and Activator of Transcription 3 (Stat3) resides in the mitochondria of cells where phosphorylation at S727 is required for optimal ETC activity and protects against stress-induced mitochondrial dysfunction. Here, we show that PHB overexpression protects against mitochondrial stress and apoptosis of cultured IECs induced by TNFα, which is a pro-inflammatory cytokine involved in IBD pathogenesis. Expression of pS727-Stat3 dominant negative eliminates protection by PHB against TNFα-induced mitochondrial stress and apoptosis. PHB interacts with pS727-Stat3 in the mitochondria of cultured IECs and in colonic epithelium from wild-type mice. Our data suggest a protective role of PHB that is dependent on pS727-Stat3 to prevent mitochondrial dysfunction in IECs. Reduced levels of PHB during IBD may be an underlying factor promoting mitochondrial dysfunction of the intestinal epithelium.
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影响因子：
9.5
作者：
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通讯作者：
Schulz R
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通讯作者：
Theiss AL