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J. Biol. Chem., Vol. 281, Issue 42, 31408-31418, October 20, 2006

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Secreted Neutral Metalloproteases of Bacillus anthracis as Candidate Pathogenic Factors^*

Myung-Chul Chung, Taissia G. Popova, Bryan A. Millis, Dhritiman V. Mukherjee, Weidong Zhou, Lance A. Liotta, Emanuel F. Petricoin, Vikas Chandhoke^¶, Charles Bailey, and Serguei G. Popov¹

From the National Center for Biodefense and Infectious Diseases, the Center for Applied Proteomics and Molecular Medicine, and the ^¶College of Arts and Sciences, George Mason University, Manassas, Virginia 20110

To evaluate the pathogenic potential of Bacillus anthracis-secreted proteases distinct from lethal toxin, two neutral zinc metalloproteases were purified to apparent homogeneity from the culture supernatant of a non-virulent delta Ames strain (pXO1^–, pXO2^–). The first (designated Npr599) is a thermolysin-like enzyme highly homologous to bacillolysins from other Bacillus species. The second (designated InhA) is a homolog of the Bacillus thuringiensis immune inhibitor A. These proteases belong to the M4 and M6 families, respectively. Both enzymes digested various substrates, including extracellular matrix proteins, endogenous inhibitors, and coagulation proteins, with some differences in specificity. In addition, InhA accelerated urokinase-mediated plasminogen activation, suggesting that InhA acts as a modulator of plasmin in the host inflammatory system. Relevant to epithelial barrier function, Npr599 and InhA significantly enhanced syndecan-1 shedding from cultured normal murine mammary gland cells without affecting their viability through stimulation of the host cell ectodomain shedding mechanism. In addition, Npr599 and InhA directly cleaved recombinant syndecan-1 fused to glutathione S-transferase. Mass spectrometric analysis suggested that the cleavage sites of Npr599 and InhA are the Asp³⁹–Asp⁴⁰ and Gly⁴⁸–Thr⁴⁹ bonds, respectively. We propose that Npr599 and InhA from B. anthracis are multifunctional pathogenic factors that may contribute to anthrax pathology through direct degradation of host tissues, increases in barrier permeability, and/or modulation of host defenses.

Received for publication, June 8, 2006 , and in revised form, August 7, 2006.

^* This work was supported by United States Department of Defense Grant DAMD 17-03-C-0122. 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 To whom correspondence should be addressed: National Center for Biodefense and Infectious Diseases, George Mason University, MSN 1H8, 10900 University Blvd., Manassas, VA 20110. Tel.: 703-993-4713; Fax: 703-993-4288; E-mail: spopov{at}gmu.edu.

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