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Anthrax lethal factor represses glucocorticoid and progesterone receptor activity.
Jeanette I Webster1, Leonardo H Tonelli, Mahtab Moayeri
1Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Summary
Anthrax lethal toxin (LeTx) represses glucocorticoid receptor (GR) activity by affecting transcription cofactors, not DNA binding. This repression may increase susceptibility to anthrax infection by reducing anti-inflammatory effects.
Area of Science:
- Molecular Biology
- Toxicology
- Endocrinology
Background:
- Nuclear receptors, such as the glucocorticoid receptor (GR), play crucial roles in regulating gene expression and maintaining physiological homeostasis.
- Bacterial toxins can interfere with cellular processes, potentially leading to disease pathogenesis.
Purpose of the Study:
- To investigate the effect of anthrax lethal toxin (LeTx) on glucocorticoid receptor (GR) transactivation.
- To elucidate the mechanism by which LeTx represses GR activity.
- To explore the implications of LeTx-induced GR repression in the context of anthrax infection.
Main Methods:
- Transient transfection assays to measure GR transactivation.
- Cellular and animal models to assess endogenous GR-regulated gene activity.
- Analysis of LeTx's effect on ligand binding and DNA binding of GR.
- Investigation of LeTx's impact on other nuclear receptors and the role of p38 MAP kinase.
Main Results:
- LeTx represses GR transactivation and endogenous GR-regulated gene activity at low concentrations.
- Repression is noncompetitive and does not involve ligand or DNA binding, suggesting cofactor involvement.
- LeTx selectively represses GR, progesterone receptor B (PR-B), and estrogen receptor alpha (ERalpha), but not mineralocorticoid receptor (MR) or ERbeta.
- LeTx-induced GR repression may be partly mediated by p38 mitogen-activated protein (MAP) kinase inactivation.
Conclusions:
- Anthrax lethal toxin (LeTx) inhibits GR activity through a mechanism involving transcription cofactors and potentially p38 MAP kinase signaling.
- The selective repression of nuclear receptors by LeTx could impair the anti-inflammatory effects of hormones.
- These findings suggest that LeTx-induced immunosuppression contributes to the pathogenesis of anthrax and has implications for treatment strategies.