The virulence-associated two-component PhoP-PhoR system controls the biosynthesis of polyketide-derived lipids in Mycobacterium tuberculosis.
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.
Gonzalo Asensio
Jesús
J
Departamento de Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, C/Domingo Miral sin numero, 50009 Zaragoza, Spain.
Maia
Catarina
C
Ferrer
Nadia L
NL
Barilone
Nathalie
N
Laval
Françoise
F
Soto
Carlos Yesid
CY
Winter
Nathalie
N
Daffé
Mamadou
M
Gicquel
Brigitte
B
Martín
Carlos
C
Jackson
Mary
M
D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000096:biosynthesis*; D018942:Macrolides / Q000378:metabolism; D016296:Mutagenesis; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000378:metabolism / Q000472:pathogenicity*; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014774:Virulence
D001426:Bacterial Proteins; D008055:Lipids; D018942:Macrolides; D011994:Recombinant Proteins; C061279:PhoR protein, Bacteria; C061064:PhoP protein, Bacteria; D011494:Protein Kinases