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J. Biol. Chem., Vol. 281, Issue 44, 33115-33126, November 3, 2006

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Coordinated Regulation of the Neisseria gonorrhoeae-truncated Denitrification Pathway by the Nitric Oxide-sensitive Repressor, NsrR, and Nitrite-insensitive NarQ-NarP^*

Tim W. Overton, Rebekah Whitehead, Ying Li, Lori A. S. Snyder, Nigel J. Saunders, Harry Smith^¶, and Jeff A. Cole¹

From the School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, the Bacterial Pathogenesis and Functional Genomics Group, the Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, and the ^¶Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom

Neisseria gonorrhoeae survives anaerobically by reducing nitrite to nitrous oxide catalyzed by the nitrite and nitric oxide reductases, AniA and NorB. P_aniA is activated by FNR (regulator of fumarate and nitrate reduction), the two-component regulatory system NarQ-NarP, and induced by nitrite; P_norB is induced by NO independently of FNR by an uncharacterized mechanism. We report the results of microarray analysis, bioinformatic analysis, and chromatin immunoprecipitation, which revealed that only five genes with readily identified NarP-binding sites are differentially expressed in narP⁺ and narP strains. These include three genes implicated in the truncated gonococcal denitrification pathway: aniA, norB, and narQ. We also report that (i) nitrite induces aniA transcription in a narP mutant; (ii) nitrite induction involves indirect inactivation by nitric oxide of a gonococcal repressor, NsrR, identified from a multigenome bioinformatic study; (iii) in an nsrR mutant, aniA, norB, and dnrN (encoding a putative reactive nitrogen species response protein) were expressed constitutively in the absence of nitrite, suggesting that NsrR is the only NO-sensing transcription factor in N. gonorrhoeae; and (iv) NO rather than nitrite is the ligand to which NsrR responds. When expressed in Escherichia coli, gonococcal NarQ and chimaeras of E. coli and gonococcal NarQ are ligand-insensitive and constitutively active: a "locked-on" phenotype. We conclude that genes involved in the truncated denitrification pathway of N. gonorrhoeae are key components of the small NarQP regulon, that NarP indirectly regulates P_norB by stimulating NO production by AniA, and that NsrR plays a critical role in enabling gonococci to evade NO generated as a host defense mechanism.

Received for publication, July 25, 2006 , and in revised form, August 17, 2006.

^* This work was funded by the UK Biotechnology and Biological Sciences Research Council Project Grant P21080 [GenBank] , and by a UK Medical Research Council PhD training studentship (to R. N. W.). The Sir William Dunn School of Pathology/Weatherall Institute of Molecular Medicine Computational Biology Research Group provided the BASE and GBrowse database bioinformatics support for this study. 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 S1 and S2.

¹ To whom correspondence should be addressed. Tel.: 44-121-414-5440; Fax: 44-121-414-5925; E-mail: j.a.cole{at}bham.ac.uk.

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