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J. Biol. Chem., Vol. 283, Issue 20, 13688-13699, May 16, 2008

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Regulatory and Structural Differences in the Cu,Zn-Superoxide Dismutases of Salmonella enterica and Their Significance for Virulence^*

Serena Ammendola, Paolo Pasquali, Francesca Pacello, Giuseppe Rotilio^¶, Margaret Castor^||, Stephen J. Libby^||, Nara Figueroa-Bossi^**1, Lionello Bossi^**1, Ferric C. Fang^||, and Andrea Battistoni²

From the Dipartimento di Biologia, Università di Roma Tor Vergata, 00133 Rome, Italy, the Dipartimento di Sanità Alimentare e Animale, Istituto Superiore di Sanità, 00161 Rome, Italy, the ^¶Centro Ricerche, IRCCS San Raffaele "La Pisana," 00163 Rome, Italy, the ^||Departments of Microbiology and Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington 98195, the ^**Centre de Génétique Moléculaire, CNRS, 91198 Gif-sur-Yvette, France, and the Consorzio Interuniversitario, "Istituto Nazionale Biostrutture e Biosistemi", Viale delle Medaglie d'Oro 305, 00136 Roma, Italy

Many of the most virulent strains of Salmonella enterica produce two distinct Cu,Zn-superoxide dismutases (SodCI and SodCII). The bacteriophage-encoded SodCI enzyme makes the greater contribution to Salmonella virulence. We have performed a detailed comparison of the functional, structural, and regulatory properties of the Salmonella SodC enzymes. Here we demonstrate that SodCI and SodCII differ with regard to specific activity, protease resistance, metal affinity, and peroxidative activity, with dimeric SodCI exhibiting superior stability and activity. In particular, monomeric SodCII is unable to retain its catalytic copper ion in the absence of zinc. We have also found that SodCI and SodCII are differentially affected by oxygen, zinc availability, and the transcriptional regulator FNR. SodCII is strongly down-regulated under anaerobic conditions and dependent on the high affinity ZnuABC zinc transport system, whereas SodCI accumulation in vitro and within macrophages is FNR-dependent. We have confirmed earlier findings that SodCII accumulation in intracellular Salmonella is negligible, whereas SodCI is strongly up-regulated in macrophages. Our observations demonstrate that differences in expression, activity, and stability help to account for the unique contribution of the bacteriophage-encoded SodCI enzyme to Salmonella virulence.

Received for publication, December 26, 2007 , and in revised form, March 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI039557 and AI50660 (to F. F.). This work was also supported by a Murst Prin Grant (to A. B.), Istituto Superiore di Sanità Grants 530/F-A23 and 530-F7/1 (to A. B. and P. P.). 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–S3.

¹ Supported by the Centre National de la Recherche Scientifique, France.

² To whom correspondence should be addressed: Dept. of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Roma, Italy. Tel.: 39-0672594372; Fax: 39-0672594311; E-mail: andrea.battistoni{at}uniroma2.it.

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