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J. Biol. Chem., Vol. 282, Issue 36, 26111-26121, September 7, 2007

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Signaling and DNA-binding Activities of the Staphylococcus aureus HssR-HssS Two-component System Required for Heme Sensing^*

From the Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232

For the important human pathogen Staphylococcus aureus, host heme is a vital source of nutrient iron during infection. Paradoxically, heme is also toxic at high concentrations and is capable of killing S. aureus. To maintain cellular heme homeostasis, S. aureus employs the coordinated actions of the heme sensing two-component system (HssRS) and the heme regulated transporter efflux pump (HrtAB). HssRS-dependent expression of HrtAB results in the alleviation of heme toxicity and tempered staphylococcal virulence. Although genetic experiments have defined the role of HssRS in the heme-dependent activation of hrtAB, the mechanism of this activation is not known. Furthermore, the global effect of HssRS on S. aureus gene expression has not been evaluated. Herein, we combine multivariable difference gel electrophoresis with mass spectrometry to identify the heme-induced cytoplasmic HssRS regulon. These experiments establish hrtAB as the major target of activation by HssRS in S. aureus. In addition, we show that signaling between the sensor histidine kinase HssS and the response regulator HssR is necessary for growth of S. aureus in high concentrations of heme. Finally, we show that a direct repeat DNA sequence within the hrtAB promoter is required for heme-induced, HssR-dependent expression driven by this promoter and that phosphorylated HssR binds to this direct repeat upon exposure of S. aureus to high concentrations of heme. Taken together, these data establish the mechanism for HssRS-dependent expression of HrtAB and, in turn, provide a functional understanding for how S. aureus avoids heme-mediated toxicity.

Received for publication, May 8, 2007 , and in revised form, June 26, 2007.

^* This work was supported in part by Vanderbilt University Medical Center development funds, the Searle Scholars Program, and United States Public Health Service Grant AI69233 from the NIAID, National Institutes of Health. 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 Table S1.

¹ Supported by NIAID, NIH Grant T32 HL069765.

² Supported by Ruth L. Kirschstein Grant NRSA AI071487 postdoctoral fellowship.

³ Holds an Investigator in Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund. To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Vanderbilt University Medical Center, 1161 21st Ave. South, MCN A-5102, Nashville, TN 37027. Tel.: 615-343-0002; Fax: 615-343-7392; E-mail: eric.skaar{at}vanderbilt.edu.

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				D. L. Stauff, D. Bagaley, V. J. Torres, R. Joyce, K. L. Anderson, L. Kuechenmeister, P. M. Dunman, and E. P. Skaar Staphylococcus aureus HrtA Is an ATPase Required for Protection against Heme Toxicity and Prevention of a Transcriptional Heme Stress Response J. Bacteriol., May 15, 2008; 190(10): 3588 - 3596. [Abstract] [Full Text] [PDF]