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J. Biol. Chem., Vol. 281, Issue 3, 1313-1316, January 20, 2006

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The Virulence-associated Two-component PhoP-PhoR System Controls the Biosynthesis of Polyketide-derived Lipids in Mycobacterium tuberculosis^*

Jesús Gonzalo Asensio, Catarina Maia12, Nadia L. Ferrer, Nathalie Barilone, Françoise Laval¶, Carlos Yesid Soto, Nathalie Winter, Mamadou Daffé¶, Brigitte Gicquel, Carlos Martín, and Mary Jackson3

From the Departamento de Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, C/Domingo Miral sin numero, 50009 Zaragoza, Spain, the Unité deGénétique Mycobactérienne, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France, and the ^¶Département "Mécanismes Moléculaires des Infections Mycobactériennes," Institut de Pharmacologie et de Biologie Structurale, UMR 5089 (Université Paul Sabatier/CNRS), 205 route de Narbonne, 31077 Toulouse Cedex, France

Two-component regulatory signal transduction systems are important elements of the adaptative response of prokaryotes to a variety of environmental stimuli. Disruption of PhoP-PhoR in Mycobacterium tuberculosis dramatically attenuates virulence, implying that this system directly and/or indirectly coordinates the expression of important virulence factors whose identity remains to be established. Interestingly, in knockingout the PhoP-PhoR two-component system in M. tuberculosis Mt103, dramatic changes in the colonial morphology, cording properties, and reactivity of the mutant strain to the basic dye neutral red, all intrinsic properties of tubercle bacilli known to correlate with virulence, were noted. Because deficiencies in the ability of the mutant to form serpentine cords and stain with the dye are likely the results of alterations of its cell envelope composition, we undertook to analyze the lipid content of phoP and phoP-phoR mutants constructed in two different strains of M. tuberculosis. Our results indicate that PhoP coordinately and positively regulates the synthesis of methyl-branched fatty acid-containing acyltrehaloses known to be restricted to pathogenic species of the M. tuberculosis complex, namely diacyltrehaloses, polyacyltrehaloses, and sulfolipids. Evidence is also provided that PhoP but not PhoR is required for the production of these lipids. This work represents an important step toward the functional characterization of PhoP-PhoR and the understanding of complex lipid synthesis in M. tuberculosis.

Received for publication, September 20, 2005 , and in revised form, December 1, 2005.

^* This work was supported in part by European Commission Contract QLK2-CT-1999-01093 ("A Cluster for Tuberculosis Vaccine Development"), the GPH-05 research program (Institut Pasteur), and the Spanish MEC (BIO2002-04133). This research project has been co-financed by the European Commission, within the 6th Framework Programme, Contract LSHP-CT-2003-503367. 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 Present address: Laboratory of Microbiology and Immunology of Infection, Inst. for Molecular and Cell Biology, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.

² Received a fellowship from Fundação para a Ciência e a Tecnologia, Portugal.

³ To whom correspondence should be addressed. Tel.: 33-1-45-68-88-77; Fax: 33-1-45-68-88-43; E-mail: mjackson{at}pasteur.fr.

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