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首页> 外文期刊>Molecular and Cellular Biology >Cellular Adaptation to Anthrax Lethal Toxin-Induced Mitochondrial Cholesterol Enrichment, Hyperpolarization, and Reactive Oxygen Species Generation through Downregulating MLN64 in Macrophages
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Cellular Adaptation to Anthrax Lethal Toxin-Induced Mitochondrial Cholesterol Enrichment, Hyperpolarization, and Reactive Oxygen Species Generation through Downregulating MLN64 in Macrophages

机译：细胞适应炭疽致死毒素诱导的线粒体胆固醇的富集，超极化和通过下调巨噬细胞中的MLN64产生活性氧。

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Cellular adaptation to different stresses related to survival and function has been demonstrated in several cell types. Anthrax lethal toxin (LeTx) induces rapid cell death, termed “pyroptosis,” by activating NLRP1b/caspase-1 in murine macrophages. We and others (S. D. Ha et al., J. Biol. Chem. 282:26275-26283, 2007; I. I. Salles et al., Proc. Natl. Acad. Sci. U. S. A. 100:12426 –12431, 2003) have shown that RAW264.7 cells preexposed to sublethal doses of LeTx become resistant to subsequent high cytolytic doses of LeTx, termed toxin-induced resistance (TIR). To date, the cellular mechanisms of pyroptosis and TIR are largely unknown. We found that LeTx caused NLRP1b/caspase-1-dependent mitochondrial dysfunction, including hyperpolarization and generation of reactive oxygen species, which was distinct from that induced by stimuli such as NLRP3-activating ATP. In TIR cells, these mitochondrial events were not detected, although caspase-1 was activated, in response to LeTx. We identified that downregulation of the late endosomal cholesterol-transferring protein MLN64 in TIR cells was involved in TIR. The downregulation of MLN64 in TIR cells was at least in part due to DNA methyltransferase 1-mediated DNA methylation. In wild-type RAW264.7 cells and primary bone marrow-derived macrophages, LeTx caused NLRP1b/caspase-1-dependent mitochondrial translocation of MLN64, resulting in cholesterol enrichment, membrane hyperpolarization, reactive oxygen species (ROS) generation, and depletion of free glutathione (GSH). This study demonstrates for the first time that MLN64 plays a key role in LeTx/caspase-1-induced mitochondrial dysfunction.
机译：在几种细胞类型中已经证明了细胞对与生存和功能有关的不同应激的适应。炭疽致死性毒素（LeTx）通过激活鼠巨噬细胞中的NLRP1b / caspase-1诱导快速的细胞死亡，称为“ pyroptosis”。我们和其他人（SD Ha等人，J。Biol。Chem。282：26275-26283，2007; II Salles等人，Proc。Natl。Acad。Sci。USA 100：12426 –12431，2003）已经表明预先暴露于亚致死剂量的LeTx的RAW264.7细胞对随后的高细胞溶解剂量的LeTx产生抗性，称为毒素诱导的抗性（TIR）。迄今为止，细胞凋亡和TIR的细胞机制尚不清楚。我们发现LeTx引起NLRP1b / caspase-1依赖的线粒体功能障碍，包括超极化和活性氧的生成，这与由诸如NLRP3激活ATP的刺激所诱导的不同。在TIR细胞中，尽管激活了caspase-1，但并未检测到这些线粒体事件，以响应LeTx。我们发现，TIR细胞中晚期内体胆固醇转移蛋白MLN64的下调与TIR有关。 TIR细胞中MLN64的下调至少部分归因于DNA甲基转移酶1介导的DNA甲基化。在野生型RAW264.7细胞和原代骨髓巨噬细胞中，LeTx导致MLRP64依赖NLRP1b / caspase-1的线粒体易位，导致胆固醇富集，膜超极化，活性氧（ROS）生成以及游离游离脂肪酸的耗尽谷胱甘肽（GSH）。这项研究首次证明MLN64在LeTx / caspase-1诱导的线粒体功能障碍中起关键作用。

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