INSERM, U895, Centre Méditerranéen de Médecine Moléculaire, C3M, Nice, 06204 Cedex 3, France.
Cell Microbiol. 2010 Jul;12(7):891-905. doi: 10.1111/j.1462-5822.2010.01438.x. Epub 2010 May 20.
We have investigated how Bacillus anthracis lethal toxin (LT) triggers caspase-3 activation and the formation of thick actin cables in human endothelial cells. By DNA array analysis we show that LT has a major impact on the cell transcriptome and we identify key host genes involved in LT cytotoxic effects. Indeed, upregulation of TRAIL and downregulation of XIAP both participate in LT-induced caspase-3 activation. LT induces a downregulation of the immediate early gene and master regulator of transcription egr1. Importantly, its re-expression in LT-intoxicated cells blocks caspase-3 activation. In parallel, we found that the formation of actin cables induced by LT occurs in the absence of direct activation of RhoA/ROCK signalling. We show that knock-down of cortactin and rhophilin-2 under conditions of calponin-1 expression defines the minimal set of genes regulated by LT for actin cable formation. Together our data establish that the modulation of the cell transcriptome by LT plays a key role in triggering human endothelial cell toxicity.
我们研究了炭疽杆菌致死毒素 (LT) 如何引发人内皮细胞中 caspase-3 的激活和厚肌动蛋白电缆的形成。通过 DNA 芯片分析，我们表明 LT 对细胞转录组有重大影响，并且我们确定了参与 LT 细胞毒性作用的关键宿主基因。事实上，TRAIL 的上调和 XIAP 的下调均参与 LT 诱导的 caspase-3 激活。LT 诱导即时早期基因和转录主调节因子 egr1 的下调。重要的是，其在 LT 中毒细胞中的重新表达阻止了 caspase-3 的激活。同时，我们发现 LT 诱导的肌动蛋白电缆的形成发生在 RhoA/ROCK 信号的直接激活缺失的情况下。我们表明，在 calponin-1 表达的情况下敲低 cortactin 和 rhophilin-2 定义了由 LT 调节形成肌动蛋白电缆的最小一组基因。总之，我们的数据表明 LT 对细胞转录组的调节在触发人内皮细胞毒性中起关键作用。
