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Science 1 May 1998:
Vol. 280. no. 5364, pp. 734 - 737
DOI: 10.1126/science.280.5364.734

Reports

Proteolytic Inactivation of MAP-Kinase-Kinase by Anthrax Lethal Factor

Nicholas S. Duesbery, Craig P. Webb, Stephen H. Leppla, Valery M. Gordon, Kurt R. Klimpel, * Terry D. Copeland, Natalie G. Ahn, Marianne K. Oskarsson, Kenji Fukasawa, Ken D. Paull, George F. Vande Woude dagger

Anthrax lethal toxin, produced by the bacterium Bacillus anthracis, is the major cause of death in animals infected with anthrax. One component of this toxin, lethal factor (LF), is suspected to be a metalloprotease, but no physiological substrates have been identified. Here it is shown that LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and MAPKK2) and that this cleavage inactivates MAPKK1 and inhibits the MAPK signal transduction pathway. The identification of a cleavage site for LF may facilitate the development of LF inhibitors.

N. S. Duesbery, C. P. Webb, T. D. Copeland, M. K. Oskarsson, G. F. Vande Woude, Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Post Office Box B, Frederick, MD 21702, USA.
S. H. Leppla, V. M. Gordon, K. R. Klimpel, National Institute of Dental Research-National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
N. G. Ahn, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of Colorado, Campus Box 215, Boulder, CO 80309, USA.
K. Fukasawa, Department of Cell Biology, University of Cincinnati, College of Medicine, P.O. Box 670521, Cincinnati, OH 45267, USA.
K. D. Paull, Division of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
*   Present address: Biopraxis, Post Office Box 9100-78, San Diego, CA 92191, USA.

dagger    To whom correspondence should be addressed.


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Receptor-specific requirements for anthrax toxin delivery into cells.
G. J. A. Rainey, D. J. Wigelsworth, P. L. Ryan, H. M. Scobie, R. J. Collier, and J. A. T. Young (2005)
PNAS 102, 13278-13283
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Protection from Anthrax Toxin-Mediated Killing of Macrophages by the Combined Effects of Furin Inhibitors and Chloroquine.
T. Komiyama, J. A. Swanson, and R. S. Fuller (2005)
Antimicrob. Agents Chemother. 49, 3875-3882
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BRAF status and mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 activity indicate sensitivity of melanoma cells to anthrax lethal toxin.
R. J. Abi-Habib, J. O. Urieto, S. Liu, S. H. Leppla, N. S. Duesbery, and A. E. Frankel (2005)
Mol. Cancer Ther. 4, 1303-1310
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Efficient synthetic inhibitors of anthrax lethal factor.
M. Forino, S. Johnson, T. Y. Wong, D. V. Rozanov, A. Y. Savinov, W. Li, R. Fattorusso, B. Becattini, A. J. Orry, D. Jung, et al. (2005)
PNAS 102, 9499-9504
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Endocrine Perturbation Increases Susceptibility of Mice to Anthrax Lethal Toxin.
M. Moayeri, J. I. Webster, J. F. Wiggins, S. H. Leppla, and E. M. Sternberg (2005)
Infect. Immun. 73, 4238-4244
   Abstract »    Full Text »    PDF »
Membrane Insertion by Anthrax Protective Antigen in Cultured Cells.
M. Qa'dan, K. A. Christensen, L. Zhang, T. M. Roberts, and R. J. Collier (2005)
Mol. Cell. Biol. 25, 5492-5498
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Anthrax Lethal Toxin Induces Endothelial Barrier Dysfunction.
J. M. Warfel, A. D. Steele, and F. D'Agnillo (2005)
Am. J. Pathol. 166, 1871-1881
   Abstract »    Full Text »    PDF »
Proteases and Signaling.
S. Wilk (2005)
Sci. STKE 2005, tr15
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Dendritic Cells Endocytose Bacillus anthracis Spores: Implications for Anthrax Pathogenesis.
K. C. Brittingham, G. Ruthel, R. G. Panchal, C. L. Fuller, W. J. Ribot, T. A. Hoover, H. A. Young, A. O. Anderson, and S. Bavari (2005)
J. Immunol. 174, 5545-5552
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Anthrax Edema Toxin Cooperates with Lethal Toxin to Impair Cytokine Secretion during Infection of Dendritic Cells.
J.-N. Tournier, A. Quesnel-Hellmann, J. Mathieu, C. Montecucco, W.-J. Tang, M. Mock, D. R. Vidal, and P. L. Goossens (2005)
J. Immunol. 174, 4934-4941
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Anthrax Lethal Toxin Blocks MAPK Kinase-Dependent IL-2 Production in CD4+ T Cells.
H. Fang, R. Cordoba-Rodriguez, C. S. R. Lankford, and D. M. Frucht (2005)
J. Immunol. 174, 4966-4971
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Human {alpha}-defensins neutralize anthrax lethal toxin and protect against its fatal consequences.
C. Kim, N. Gajendran, H.-W. Mittrucker, M. Weiwad, Y.-H. Song, R. Hurwitz, M. Wilmanns, G. Fischer, and S. H. E. Kaufmann (2005)
PNAS 102, 4830-4835
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Purified Bacillus anthracis Lethal Toxin Complex Formed in Vitro and during Infection Exhibits Functional and Biological Activity.
R. G. Panchal, K. M. Halverson, W. Ribot, D. Lane, T. Kenny, T. G. Abshire, J. W. Ezzell, T. A. Hoover, B. Powell, S. Little, et al. (2005)
J. Biol. Chem. 280, 10834-10839
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GeneChip Analyses of Global Transcriptional Responses of Murine Macrophages to the Lethal Toxin of Bacillus anthracis.
J. E. Comer, C. L. Galindo, A. K. Chopra, and J. W. Peterson (2005)
Infect. Immun. 73, 1879-1885
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Bacterial toxins and the immune system: show me the in vivo targets.
J. E. Galan (2005)
J. Exp. Med. 201, 321-323
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Anthrax toxins suppress T lymphocyte activation by disrupting antigen receptor signaling.
S. R. Paccani, F. Tonello, R. Ghittoni, M. Natale, L. Muraro, M. M. D'Elios, W.-J. Tang, C. Montecucco, and C. T. Baldari (2005)
J. Exp. Med. 201, 325-331
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A High-Affinity Monoclonal Antibody to Anthrax Protective Antigen Passively Protects Rabbits before and after Aerosolized Bacillus anthracis Spore Challenge.
N. Mohamed, M. Clagett, J. Li, S. Jones, S. Pincus, G. D'Alia, L. Nardone, M. Babin, G. Spitalny, and L. Casey (2005)
Infect. Immun. 73, 795-802
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Murine Macrophage Transcriptional Responses to Bacillus anthracis Infection and Intoxication.
N. H. Bergman, K. D. Passalacqua, R. Gaspard, L. M. Shetron-Rama, J. Quackenbush, and P. C. Hanna (2005)
Infect. Immun. 73, 1069-1080
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Anthrolysin O and Other Gram-positive Cytolysins Are Toll-like Receptor 4 Agonists.
J. M. Park, V. H. Ng, S. Maeda, R. F. Rest, and M. Karin (2004)
J. Exp. Med. 200, 1647-1655
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Involvement of Domain II in Toxicity of Anthrax Lethal Factor.
X. Liang, J. J. Young, S. A. Boone, D. S. Waugh, and N. S. Duesbery (2004)
J. Biol. Chem. 279, 52473-52478
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Rabbit and Nonhuman Primate Models of Toxin-Targeting Human Anthrax Vaccines.
A. J. Phipps, C. Premanandan, R. E. Barnewall, and M. D. Lairmore (2004)
Microbiol. Mol. Biol. Rev. 68, 617-629
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Functional Analysis of Bacillus anthracis Protective Antigen by Using Neutralizing Monoclonal Antibodies.
F. Brossier, M. Levy, A. Landier, P. Lafaye, and M. Mock (2004)
Infect. Immun. 72, 6313-6317
   Abstract »    Full Text »    PDF »
A cationic lipid-formulated plasmid DNA vaccine confers sustained antibody-mediated protection against aerosolized anthrax spores.
G. Hermanson, V. Whitlow, S. Parker, K. Tonsky, D. Rusalov, M. Ferrari, P. Lalor, M. Komai, R. Mere, M. Bell, et al. (2004)
PNAS 101, 13601-13606
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