title: An oligopeptide transporter of Mycobacterium tuberculosis regulates cytokine release and apoptosis of infected macrophages.
abstract: BACKGROUND
  The Mycobacterium tuberculosis genome encodes two peptide transporters encoded by Rv3665c-Rv3662c and Rv1280c-Rv1283c. Both belong to the family of ABC transporters containing two nucleotide-binding subunits, two integral membrane proteins and one substrate-binding polypeptide. However, little is known about their functions in M. tuberculosis. Here we report functional characterization of the Rv1280c-Rv1283c-encoded transporter and its substrate-binding polypeptide OppA(MTB).
  
  
  RESULTS
  OppA(MTB) was capable of binding the tripeptide glutathione and the nonapeptide bradykinin, indicative of a somewhat broad substrate specificity. Amino acid residues G109, N110, N230, D494 and F496, situated at the interface between domains I and III of OppA, were required for optimal peptide binding. Complementaton of an oppA knockout mutant of M. smegmatis with OppA(MTB) confirmed the role of this transporter in importing glutathione and the importance of the aforesaid amino acid residues in peptide transport. Interestingly, this transporter regulated the ability of M. tuberculosis to lower glutathione levels in infected compared to uninfected macrophages. This ability was partly offset by inactivation of oppD. Concomitantly, inactivation of oppD was associated with lowered levels of methyl glyoxal in infected macrophages and reduced apoptosis-inducing ability of the mutant. The ability to induce the production of the cytokines IL-1beta, IL-6 and TNF-alpha was also compromised after inactivation of oppD.
  
  
  CONCLUSIONS
  Taken together, these studies uncover the novel observations that this peptide transporter modulates the innate immune response of macrophages infected with M. tuberculosis.
authors.affiliation: Unité de Génétique Mycobactérienne, Institut Pasteur, Paris, France.
authors.forename: Arunava
authors.initials: A
authors.lastname: Dasgupta
authors.forename: Kamakshi
authors.initials: K
authors.lastname: Sureka
authors.forename: Devrani
authors.initials: D
authors.lastname: Mitra
authors.forename: Baisakhee
authors.initials: B
authors.lastname: Saha
authors.forename: Sourav
authors.initials: S
authors.lastname: Sanyal
authors.forename: Amit K
authors.initials: AK
authors.lastname: Das
authors.forename: Parul
authors.initials: P
authors.lastname: Chakrabarti
authors.forename: Mary
authors.initials: M
authors.lastname: Jackson
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gicquel
authors.forename: Manikuntala
authors.initials: M
authors.lastname: Kundu
authors.forename: Joyoti
authors.initials: J
authors.lastname: Basu
mesh_terms: D017209:Apoptosis; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D004252:DNA Mutational Analysis; D055786:Gene Knockout Techniques; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism* / Q000382:microbiology; D008958:Models, Molecular; D009154:Mutation; D020102:Mycobacterium smegmatis / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000378:metabolism* / Q000502:physiology; D011765:Pyruvaldehyde / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D016207:Cytokines; D008074:Lipoproteins; C046506:oligopeptide-binding protein, bacteria; D011765:Pyruvaldehyde; D005978:Glutathione
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