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J. Biol. Chem., Vol. 281, Issue 38, 28039-28047, September 22, 2006

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Maintenance of Nitric Oxide and Redox Homeostasis by the Salmonella Flavohemoglobin Hmp^*

Iel-Soo Bang, Limin Liu¹, Andrés Vazquez-Torres^¶, Marie-Laure Crouch, Jonathan S. Stamler, and Ferric C. Fang²

From the Departments of Microbiology and Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington 98195, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, and ^¶Department of Microbiology, University of Colorado Health Sciences Center, Aurora, Colorado 80010

Intracellular pathogens must resist the antimicrobial actions of nitric oxide (NO·) produced by host cells. To this end pathogens possess several NO·-metabolizing enzymes. Here we show that the flavohemoglobin Hmp is the principal enzyme responsible for aerobic NO· metabolism by Salmonella enterica serovar typhimurium. We further show that Hmp is required for Salmonella virulence in mice, in contrast to S-nitrosoglutathione reductase, flavorubredoxin, or cytochrome c nitrite reductase. Abrogation of murine-inducible NO· synthase restores virulence to hmp mutant bacteria. In the presence of nitrosative stress, Hmp-deficient Salmonella exhibits reduced NO· consumption, impaired growth, increased protein S-nitrosylation, and filamentous morphology. However, under aerobic conditions in the absence of nitrosative stress, elevated hmp expression increases S. typhimurium susceptibility to hydrogen peroxide. Both the heme binding and flavoreductase domains are required for resistance to NO·, whereas the flavoreductase domain is responsible for iron-dependent susceptibility to oxidative stress. This provides a rationale for the regulation of hmp expression by the transcriptional repressor NsrR in response to both nitrosative stress and intracellular free iron concentration. The Hmp flavohemoglobin plays a central role in the response of Salmonella to nitrosative stress but requires precise regulation to avoid the exacerbation of oxidative stress that can result if electrons are shuttled to extraneous iron.

Received for publication, May 30, 2006 , and in revised form, July 20, 2006.

^* This work was supported in part by National Institutes of Health Research Grants AI39557 and AI50660 (to F. C. F.) and AI54959 (to A. V.-T.) and by the Howard Hughes Medical Institute. 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 Tables 1 and 2.

¹ Present address: Dept. of Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143.

² To whom correspondence should be addressed: Depts. of Microbiology and Laboratory Medicine, University of Washington School of Medicine, 1959 Pacific St NE, Box 357242, Seattle, WA 98195-7242. Tel.: 206-221-6770; Fax: 206-616-1575; E-mail: fcfang{at}u.washington.edu.

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