Novel Repression of the Glucocorticoid Receptor by Anthrax Lethal Toxin

doi:10.1196/annals.1321.003

^aSection on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, and ^bNational Institute of Autoimmune and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA

Address for correspondence: Esther M. Sternberg, M.D., Section on Neuroendocrine Immunology and Behavior, NIMH, NIH, Bldg. 36, Rm. 1A23, 36 Convent Drive, MSC 4020, Bethesda, MD 20892-4020.Voice: +1 301-402-2773; fax: +1 301-496-6095. sternbee{at}mail.nih.gov
Ann. N.Y. Acad. Sci. 1024: 9-23 (2004).

Death from anthrax has been reported to occur from systemicshock. The lethal toxin (LeTx) is the major effector of anthraxmortality. Although the mechanism of entry of this toxin intocells is well understood, its actions once inside the cell arenot as well understood. LeTx is known to cleave and inactivateMAPKKs. We have recently shown that LeTx represses the glucocorticoidreceptor (GR) both in vitro and in vivo. This repression ispartial and specific, repressing the glucocorticoid, progesterone,and estrogen receptor ${alpha}$ , but not the mineralocorticoid or estrogenreceptor ß. This toxin does not affect GR ligand orDNA binding, and we have suggested that it may function by removing/inactivatingone or more of the many cofactors involved in nuclear hormonereceptor signaling. Although the precise involvement of thisnuclear hormone receptor repression in LeTx toxicity is unknown,examples of blunted HPA axis and glucocorticoid signaling innumerous autoimmune/inflammatory diseases suggest that suchrepression of critically important receptors could have deleteriouseffects on health.