Anthrax lethal toxin represses glucocorticoid receptor (GR) transactivation by inhibiting GR-DNA binding in vivo

Anthrax lethal factor (LF) is a non-competitive repressor of glucocorticoid (GR) and progesterone receptor (PR) transactivation. This repression was shown to be specific and selective and was dependent on promoter context and receptor subtype. Anthrax lethal toxin (LeTx) selectively repressed GR-mediated transactivation but not transrepression. The DNA binding region of GR was required for repression by LeTx and LeTx prevented GR-DNA binding in vivo, which had downstream consequences on polymerase II binding and histone acetylation. In addition, LeTx also prevented the accessory protein C/EBP from binding to a GR-responsive promoter. We hypothesize that LeTx may remove/inactivate one of the many co-factors or accessory proteins that are required to stabilize the GR-DNA complex. These findings enhance the current knowledge of the molecular mechanism by which the anthrax lethal factor represses nuclear hormone receptors and could provide an approach to overcome some of LeTx's effects.