Novel repression of the glucocorticoid receptor by anthrax lethal toxin.
Death from anthrax has been reported to occur from systemic shock. The lethal toxin (LeTx) is the major effector of anthrax mortality. Although the mechanism of entry of this toxin into cells is well understood, its actions once inside the cell are not as well understood. LeTx is known to cleave and inactivate MAPKKs. We have recently shown that LeTx represses the glucocorticoid receptor (GR) both in vitro and in vivo. This repression is partial and specific, repressing the glucocorticoid, progesterone, and estrogen receptor alpha, but not the mineralocorticoid or estrogen receptor beta. This toxin does not affect GR ligand or DNA binding, and we have suggested that it may function by removing/inactivating one or more of the many cofactors involved in nuclear hormone receptor signaling. Although the precise involvement of this nuclear hormone receptor repression in LeTx toxicity is unknown, examples of blunted HPA axis and glucocorticoid signaling in numerous autoimmune/inflammatory diseases suggest that such repression of critically important receptors could have deleterious effects on health.
Webster
Jeanette I
JI
Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, NIH, Bethesda, MD 20892-4020, USA.
Moayeri
Mahtab
M
Sternberg
Esther M
EM
D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D007154:Immune System Diseases / Q000209:etiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; C030325:anthrax toxin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases