Transcriptome dysregulation by anthrax lethal toxin plays a key role in induction of human endothelial cell cytotoxicity.
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.
Rolando
Monica
M
INSERM, U895, Centre Méditerranéen de Médecine Moléculaire, C3M, Nice, 06204 Cedex 3, France.
Stefani
Caroline
C
Flatau
Gilles
G
Auberger
Patrick
P
Mettouchi
Amel
A
Mhlanga
Musa
M
Rapp
Ulf
U
Galmiche
Antoine
A
Lemichez
Emmanuel
E
D000942:Antigens, Bacterial / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001427:Bacterial Toxins / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C030325:anthrax toxin; D053148:Caspase 3