Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.
Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.
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DOI：
10.1371/journal.ppat.1000516
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发表时间：
2009-07
期刊：
影响因子：
6.7
通讯作者：
Rood JI
中科院分区：
文献类型：
--
作者：
Kennedy CL;Smith DJ;Lyras D;Chakravorty A;Rood JI
程序性坏死是一种细胞死亡机制，已被描述为神经元兴奋性毒性和缺血/再灌注损伤，但尚未在暴露于细菌外毒素的背景下进行广泛研究。败血性梭菌的α-毒素是一种β-桶孔形成毒素和强效细胞毒素;然而，其诱导细胞死亡的机制尚未详细阐明。我们报道了α-毒素在小鼠成肌细胞中形成Ca 2+渗透孔，导致细胞内Ca 2+水平升高。这种Ca 2+内流不诱导细胞凋亡，如已描述的其他小孔形成毒素，但级联事件与程序性坏死一致。钙离子内流与钙蛋白酶激活和组织蛋白酶从溶酶体释放有关。我们还观察到线粒体活性失调，导致ROS水平增加，ATP水平显著降低。最后，发现免疫刺激性组蛋白结合蛋白HMGB 1从α毒素处理的细胞核中释放。总的来说，这些数据表明，α-毒素启动多方面的坏死细胞死亡反应，这与其在C.败血症介导的肌坏死和败血症。我们推测，细胞中毒与孔形成毒素可能是一个主要的机制，程序性坏死诱导。 败血性梭菌是一种高毒性病原体，可引起自发性气性坏疽或梭菌性肌坏死。C.败血症是一种β-桶毒素，α-毒素，在宿主细胞膜上形成小孔。这种毒素通常被描述为溶血素，因为这些孔的形成会由于膜破坏而导致红细胞溶解。然而，该描述未认识到可能在对α毒素更敏感的有核宿主细胞中观察到的其他效应。我们通过用纯化的毒素处理生理相关的肌肉细胞系并使用各种测定法监测反应，研究了有核细胞如何对α-毒素作出反应。我们观察到α-毒素介导的程序性细胞坏死，最终导致免疫刺激分子HMGB 1的释放。这种细胞死亡诱导机制与C.败血症介导的肌坏死，以及经常导致高死亡率的压倒性败血症。这些结果代表了在理解β桶成孔毒素的毒性以及它们如何导致坏死和全身性疾病病理学方面的重要进展。
Programmed necrosis is a mechanism of cell death that has been described for neuronal excitotoxicity and ischemia/reperfusion injury, but has not been extensively studied in the context of exposure to bacterial exotoxins. The α-toxin of Clostridium septicum is a β-barrel pore-forming toxin and a potent cytotoxin; however, the mechanism by which it induces cell death has not been elucidated in detail. We report that α-toxin formed Ca2+-permeable pores in murine myoblast cells, leading to an increase in intracellular Ca2+ levels. This Ca2+ influx did not induce apoptosis, as has been described for other small pore-forming toxins, but a cascade of events consistent with programmed necrosis. Ca2+ influx was associated with calpain activation and release of cathepsins from lysosomes. We also observed deregulation of mitochondrial activity, leading to increased ROS levels, and dramatically reduced levels of ATP. Finally, the immunostimulatory histone binding protein HMGB1 was found to be released from the nuclei of α-toxin-treated cells. Collectively, these data show that α-toxin initiates a multifaceted necrotic cell death response that is consistent with its essential role in C. septicum-mediated myonecrosis and sepsis. We postulate that cellular intoxication with pore-forming toxins may be a major mechanism by which programmed necrosis is induced. Clostridium septicum is a highly virulent pathogen that causes spontaneous gas gangrene or clostridial myonecrosis. The essential virulence factor of C. septicum is a β-barrel toxin, α-toxin, that forms small pores in host cell membranes. This toxin is frequently described as a hemolysin, because the formation of these pores causes lysis of red blood cell cells due to membrane disruption. However, this description does not recognize additional effects that may be observed in nucleated host cells, which are more sensitive to α-toxin. We investigated how nucleated cells responded to α-toxin by treating a physiologically relevant muscle cell line with purified toxin and monitoring the response using various assays. We observed α-toxin-mediated programmed cellular necrosis that culminated in the release of the immunostimulatory molecule, HMGB1. This mechanism of cell death induction is consistent with the extensive necrosis that is evident in C. septicum-mediated myonecrosis and with the overwhelming sepsis that frequently contributes to the high mortality rate. These results represent an important advance in the understanding of the toxicity of β-barrel pore-forming toxins and how they may contribute to necrotic and systemic disease pathology.
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影响因子：
5.5
作者：
Duan, Yuntao;Gross, Robert A.;Sheu, Shey-Shing
通讯作者：
Sheu, Shey-Shing
影响因子：
20.1
作者：
Inserte, J;Garcia-Dorado, D;Soler-Soler, J
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影响因子：
3.1
作者：
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通讯作者：
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影响因子：
64.5
作者：
Gurcel, Laure;Abrami, Laurence;van der Goot, F. Gisou
通讯作者：
van der Goot, F. Gisou
影响因子：
12.4
作者：
Essmann, F;Bantel, H;Jänicke, RU
通讯作者：
Jänicke, RU