Present addresses: MPI for Biochemistry, Department of Molecular Biology, Am Klopferspitz 18, D-82152 Martinsried, München, Germany;
Transcriptome dysregulation by anthrax lethal toxin plays a key role in induction of human endothelial cell cytotoxicity
Article first published online: 20 JAN 2010
© 2010 Blackwell Publishing Ltd
Volume 12, Issue 7, pages 891–905, July 2010
How to Cite
Rolando, M., Stefani, C., Flatau, G., Auberger, P., Mettouchi, A., Mhlanga, M., Rapp, U., Galmiche, A. and Lemichez, E. (2010), Transcriptome dysregulation by anthrax lethal toxin plays a key role in induction of human endothelial cell cytotoxicity. Cellular Microbiology, 12: 891–905. doi: 10.1111/j.1462-5822.2010.01438.x
- Issue published online: 7 JUN 2010
- Article first published online: 20 JAN 2010
- Received 7 September, 2009; revised 12 January, 2010; accepted 12 January, 2010.
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.