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J. Biol. Chem., Vol. 282, Issue 36, 26275-26283, September 7, 2007
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From the
Department of Microbiology and Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario N6G 2V4, Canada and ¶Department of Immunology, The Scripps Research Institute, La Jolla, California 92037
Anthrax lethal toxin (LeTx) induces rapid cell death of RAW246.7 macrophages. We recently found that a small population of these macrophages is spontaneously and temporally refractory to LeTx-induced cytotoxicity. Analysis of genome-wide transcripts of a resistant clone before and after regaining LeTx sensitivity revealed that a reduction of two closely related mitochondrial proteins, Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) and Bnip3-like (Bnip3L), correlates with LeTx resistance. Down-regulation of Bnip3 and Bnip3L was also found in "toxin-induced resistance" whereby sublethal doses of LeTx induce resistance to subsequent exposure to cytolytic toxin doses. The role of Bnip3 and Bnip3L in LeTx-induced cell death was confirmed by showing that overexpression of either Bnip3 or Bnip3L rendered the resistant cells susceptible to LeTx, whereas down-regulation of Bnip3 and Bnip3L in wild-type macrophages conferred resistance. The down-regulation of Bnip3 and Bnip3L mRNAs by LeTx occurred at both transcriptional and mRNA stability levels. Inhibition of the p38 pathway by lethal factor was responsible for the destabilization of Bnip3/Bnip3L mRNAs as confirmed by showing that p38 inhibitors stabilized Bnip3 and Bnip3L mRNAs and conferred resistance to LeTx cytotoxicity. Therefore, Bnip3/Bnip3L play a crucial role in LeTx-induced cytotoxicity, and down-regulation of Bnip3/Bnip3L is a mechanism of spontaneous or toxin-induced resistance of macrophages.
Received for publication, May 3, 2007 , and in revised form, June 22, 2007.
* This work was supported in part by Canadian Institute of Health Research Grant MOP68841 (to S. O. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported by a Canada graduate award from the Canadian Institutes of Health Research.
2 Holds a Canada research chair in infectious diseases and microbial pathogenesis.
3 To whom correspondence should be addressed: Dept. of Microbiology and Immunology, University of Western Ontario, London, Ontario N6G 2V4, Canada. Tel.: 519-850-2961; Fax: 519-661-2046; E-mail: sung.kim{at}schulich.uwo.ca.
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