title: Differential roles for the Co(2+) /Ni(2+) transporting ATPases, CtpD and CtpJ, in Mycobacterium tuberculosis virulence.
abstract: The genome of Mycobacterium tuberculosis encodes two paralogous P1 B 4 -ATPases, CtpD (Rv1469) and CtpJ (Rv3743). Both proteins showed ATPase activation by Co(2+) and Ni(2+) , and both appear to be required for metal efflux from the cell. However, using a combination of biochemical and genetic studies we found that these proteins play non-redundant roles in virulence and metal efflux. CtpJ expression is induced by Co(2+) and this protein possesses a relatively high turnover rate. A ctpJ deletion mutant accumulated Co(2+) , indicating that this ATPase controls cytoplasmic metal levels. In contrast, CtpD expression is induced by redox stressors and this protein displays a relatively low turnover rate. A ctpD mutant failed to accumulate metal, suggesting an alternative cellular function. ctpD is cotranscribed with two thioredoxin genes trxA (Rv1470), trxB (Rv1471), and an enoyl-coA hydratase (Rv1472), indicating a possible role for CtpD in the metallation of these redox-active proteins. Supporting this, in vitro metal binding assays showed that TrxA binds Co(2+) and Ni(2+) . Mutation of ctpD, but not ctpJ, reduced bacterial fitness in the mouse lung, suggesting that redox maintenance, but not Co(2+) accumulation, is important for growth in vivo.
authors.affiliation: Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA, 01609, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Raimunda
authors.forename: Jarukit E
authors.initials: JE
authors.lastname: Long
authors.forename: Teresita
authors.initials: T
authors.lastname: Padilla-Benavides
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sassetti
authors.forename: José M
authors.initials: JM
authors.lastname: Argüello
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D003035:Cobalt / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D056084:Genetic Fitness; D016680:Genome, Bacterial; D008168:Lung / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000502:physiology; D009532:Nickel / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D013879:Thioredoxins; D014376:Tuberculosis / Q000382:microbiology*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D026361:Reactive Nitrogen Species; D037521:Virulence Factors; D003035:Cobalt; D013879:Thioredoxins; D009532:Nickel; D000251:Adenosine Triphosphatases