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J. Biol. Chem., Vol. 282, Issue 47, 34260-34267, November 23, 2007

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Proteasomes Control Caspase-1 Activation in Anthrax Lethal Toxin-mediated Cell Killing^*

From the Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

Activation of caspase-1 through the inflammasome protein Nalp1b controls anthrax lethal toxin (LT)-induced necrosis in murine macrophages. In this study we analyzed physiological changes controlled by caspase-1 in LT-treated murine macrophages. The caspase-1 inhibitor Boc-D-cmk blocked caspase-1 activity and membrane impairment in LT-treated cells. To determine the relationship between caspase-1 activation and membrane integrity, we added Boc-D-cmk to J774A.1 macrophages at different time points following LT exposure. Remarkably, Boc-D-cmk rescued LT-treated macrophages, even when added at the peak of caspase-1 activation. Late addition of the caspase-1 inhibitor reversed the losses of plasma membrane integrity and metabolic activity in these cells. Similar results were obtained with the proteasome inhibitor MG132, one of the most potent inhibitors of LT toxicity. LT-treated macrophages displaying evidence of membrane impairment recovered upon the addition of MG132, mirroring the Boc-D-cmk response. Strikingly, late addition of proteasome inhibitors also abrogated caspase-1 activity in LT-treated macrophages. Proteasomal control of caspase-1 activity and membrane impairment, however, was restricted to LT-induced cytolysis, because proteasome inhibitors did not block caspase-1 activation and cell death triggered by lipopolysaccharide and nigericin. Our findings indicate that proteasome inhibitors do not target caspase-1 directly but instead control an upstream event in LT-treated macrophages leading to caspase-1 activation. Taken together, caspase-1-mediated necrosis appears to be tightly controlled and differentially regulated by proteasomes depending on the source of caspase-1 induction.

Received for publication, July 11, 2007 , and in revised form, August 22, 2007.

^* This work was supported in part by FACS Core resources of the Albert Einstein College of Medicine Center for AIDS Research. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by Grant AI057158 from the Northeast Biodefense Center-Lipkin.

² Supported by National Institutes of Health Medical Scientist Training Grant T32GM007288.

³ To whom correspondence should be addressed. Tel.: 718-430-3079; Fax: 718-430-8711; E-mail: brojatsc{at}aecom.yu.edu.

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