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Infection and Immunity, March 2009, p. 1262-1271, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.01032-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Anthrax Lethal Toxin Triggers the Formation of a Membrane-Associated Inflammasome Complex in Murine Macrophages

Adel M. Nour,¹ Yee-Guide Yeung,² Laura Santambrogio,³ Eric D. Boyden,⁴ E. Richard Stanley,² and Jürgen Brojatsch^1*

Department of Microbiology and Immunology,¹ Department of Developmental and Molecular Biology,² Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461,³ Department of Orthopedics, Children's Hospital Boston, Boston, Massachusetts 02115⁴

Received 19 August 2008/ Returned for modification 17 September 2008/ Accepted 23 December 2008

Multiple microbial components trigger the formation of an inflammasome complex that contains pathogen-specific nucleotide oligomerization and binding domain (NOD)-like receptors (NLRs), caspase-1, and in some cases the scaffolding protein ASC. The NLR protein Nalp1b has been linked to anthrax lethal toxin (LT)-mediated cytolysis of murine macrophages. Here we demonstrate that in unstimulated J774A.1 macrophages, caspase-1 and Nalp1b are membrane associated and part of 200- and 800-kDa complexes, respectively. LT treatment of these cells resulted in caspase-1 recruitment to the Nalp1b-containing complex, concurrent with processing of cytosolic caspase-1 substrates. We further demonstrated that Nalp1b and caspase-1 are able to interact with each other. Intriguingly, both caspase-1 and Nalp1b were membrane associated, while the caspase-1 substrate interleukin-18 was cytosolic. Caspase-1-associated inflammasome components included, besides Nalp1b, proinflammatory caspase-11 and the caspase-1 substrate -enolase. Asc was not part of the Nalp1b inflammasome in LT-treated macrophages. Taken together, our findings suggest that LT triggers the formation of a membrane-associated inflammasome complex in murine macrophages, resulting in cleavage of cytosolic caspase-1 substrates and cell death.

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* Corresponding author. Mailing address: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Golding 404, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-3079. Fax: (718) 430-8711. E-mail: brojatsc{at}aecom.yu.edu

Published ahead of print on 5 January 2009.

Editor: J. B. Bliska

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Infection and Immunity, March 2009, p. 1262-1271, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.01032-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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