Fatty acid metabolism plays an important role in the survival and pathogenesis of . Lipids are assumed to be the major source of energy during dormancy. Here, we report the characterization of a starvation-inducible, lipid-responsive transcriptional regulator, , divergently transcribed from the probable operon. The striking difference in the transcriptional regulatory apparatus between mycobacteria and other well-studied organisms, such as , is the organization of mycobacterial promoters. Mycobacterial promoters have diverse architectures and most of these promoters function inefficiently in In this study, we characterized the promoter elements of along with the sigma factors required for transcription initiation. promoter activity increased under nutrient starvation conditions and was transcribed via two promoters: the promoter proximal to the translational start site was active under standard growth conditions, whilst both promoters contributed to the increased activity seen during starvation, with the major contribution from the distal promoter. Furthermore, Rv0494 translation initiated at a codon located 9 bp downstream of the annotated start codon. Rv0494 bound to its upstream sequence to auto-regulate its own expression; this binding was responsive to long-chain fatty acyl-CoA molecules. We further report Rv0494-mediated transcriptional regulation of the gene – a probable transmembrane ATP-binding transporter encoding gene.


Article metrics loading...

Loading full text...

Full text loading...



  1. Agari Y., Agari K., Sakamoto K., Kuramitsu S., Shinkai A.(2011). TetR-family transcriptional repressor Thermus thermophilus FadR controls fatty acid degradation. Microbiology 157, 15891601. [View Article][PubMed] [Google Scholar]
  2. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J.(1990). Basic local alignment search tool. J Mol Biol 215, 403410. [View Article][PubMed] [Google Scholar]
  3. Baek S. H., Li A. H., Sassetti C. M.(2011). Metabolic regulation of mycobacterial growth and antibiotic sensitivity. PLoS Biol 9, e1001065. [View Article][PubMed] [Google Scholar]
  4. Balázsi G., Heath A. P., Shi L., Gennaro M. L.(2008). The temporal response of the Mycobacterium tuberculosis gene regulatory network during growth arrest. Mol Syst Biol 4, 225. [View Article][PubMed] [Google Scholar]
  5. Betts J. C., Lukey P. T., Robb L. C., McAdam R. A., Duncan K.(2002). Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol 43, 717731. [View Article][PubMed] [Google Scholar]
  6. Bharati B. K., Swetha R. K., Chatterji D.(2013). Identification and characterization of starvation induced msdgc-1 promoter involved in the c-di-GMP turnover. Gene 528, 99108. [View Article][PubMed] [Google Scholar]
  7. Biswas R. K., Dutta D., Tripathi A., Feng Y., Banerjee M., Singh B. N.(2013). Identification and characterization of Rv0494: a fatty acid-responsive protein of the GntR/FadR family from Mycobacterium tuberculosis. Microbiology 159, 913923. [View Article][PubMed] [Google Scholar]
  8. Braibant M., Gilot P., Content J.(2000). The ATP binding cassette (ABC) transport systems of Mycobacterium tuberculosis. FEMS Microbiol Rev 24, 449467. [View Article][PubMed] [Google Scholar]
  9. Brown R. N., Gulig P. A.(2008). Regulation of fatty acid metabolism by FadR is essential for Vibrio vulnificus to cause infection of mice. J Bacteriol 190, 76337644. [View Article][PubMed] [Google Scholar]
  10. Casali N., White A. M., Riley L. W.(2006). Regulation of the Mycobacterium tuberculosis mce1 operon. J Bacteriol 188, 441449. [View Article][PubMed] [Google Scholar]
  11. Cole S. T., Brosch R., Parkhill J., Garnier T., Churcher C., Harris D., Gordon S. V., Eiglmeier K., Gas S.& other authors (1998). Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537544. [View Article][PubMed] [Google Scholar]
  12. DiRusso C. C., Tsvetnitsky V., Højrup P., Knudsen J.(1998). Fatty acyl-CoA binding domain of the transcription factor FadR. Characterization by deletion, affinity labeling, and isothermal titration calorimetry. J Biol Chem 273, 3365233659. [View Article][PubMed] [Google Scholar]
  13. Fulton D. L., Li Y. Y., Laird M. R., Horsman B. G., Roche F. M., Brinkman F. S.(2006). Improving the specificity of high-throughput ortholog prediction. BMC Bioinformatics 7, 270. [View Article][PubMed] [Google Scholar]
  14. Galagan J. E., Minch K., Peterson M., Lyubetskaya A., Azizi E., Sweet L., Gomes A., Rustad T., Dolganov G.& other authors (2013). The Mycobacterium tuberculosis regulatory network and hypoxia. Nature 499, 178183. [View Article][PubMed] [Google Scholar]
  15. Georgi T., Engels V., Wendisch V. F.(2008). Regulation of l-lactate utilization by the FadR-type regulator LldR of Corynebacterium glutamicum. J Bacteriol 190, 963971. [View Article][PubMed] [Google Scholar]
  16. Haydon D. J., Guest J. R.(1991). A new family of bacterial regulatory proteins. FEMS Microbiol Lett 79, 291296. [View Article][PubMed] [Google Scholar]
  17. Korduláková J., Gilleron M., Mikusova K., Puzo G., Brennan P. J., Gicquel B., Jackson M.(2002). Definition of the first mannosylation step in phosphatidylinositol mannoside synthesis. PimA is essential for growth of mycobacteria. J Biol Chem 277, 3133531344. [View Article][PubMed] [Google Scholar]
  18. Leoni L., Orsi N., de Lorenzo V., Visca P.(2000). Functional analysis of PvdS, an iron starvation sigma factor of Pseudomonas aeruginosa. J Bacteriol 182, 14811491. [View Article][PubMed] [Google Scholar]
  19. Loebel R. O., Shorr E., Richardson H. B.(1933a). The influence of foodstuffs upon the respiratory metabolism and growth of human tubercle bacilli. J Bacteriol 26, 139166.[PubMed] [Google Scholar]
  20. Loebel R. O., Shorr E., Richardson H. B.(1933b). The influence of adverse conditions upon the respiratory metabolism and growth of human tubercle bacilli. J Bacteriol 26, 167200.[PubMed] [Google Scholar]
  21. McClure W. R.(1985). Mechanism and control of transcription initiation in prokaryotes. Annu Rev Biochem 54, 171204. [View Article][PubMed] [Google Scholar]
  22. Ninfa A. J., Reitzer L. J., Magasanik B.(1987). Initiation of transcription at the bacterial glnAp2 promoter by purified E. coli components is facilitated by enhancers. Cell 50, 10391046. [View Article][PubMed] [Google Scholar]
  23. Pandey A. K., Sassetti C. M.(2008). Mycobacterial persistence requires the utilization of host cholesterol. Proc Natl Acad Sci U S A 105, 43764380. [View Article][PubMed] [Google Scholar]
  24. Papavinasasundaram K. G., Anderson C., Brooks P. C., Thomas N. A., Movahedzadeh F., Jenner P. J., Colston M. J., Davis E. O.(2001). Slow induction of RecA by DNA damage in Mycobacterium tuberculosis. Microbiology 147, 32713279.[PubMed] [Google Scholar]
  25. Rigali S., Derouaux A., Giannotta F., Dusart J.(2002). Subdivision of the helix-turn-helix GntR family of bacterial regulators in the FadR, HutC, MocR, and YtrA subfamilies. J Biol Chem 277, 1250712515. [View Article][PubMed] [Google Scholar]
  26. Rohde K., Yates R. M., Purdy G. E., Russell D. G.(2007). Mycobacterium tuberculosis and the environment within the phagosome. Immunol Rev 219, 3754. [View Article][PubMed] [Google Scholar]
  27. Rojo F.(1999). Repression of transcription initiation in bacteria. J Bacteriol 181, 29872991.[PubMed] [Google Scholar]
  28. Ross W., Salomon J., Holmes W. M., Gourse R. L.(1999). Activation of Escherichia coli leuV transcription by FIS. J Bacteriol 181, 38643868.[PubMed] [Google Scholar]
  29. Santangelo M. P., Blanco F. C., Bianco M. V., Klepp L. I., Zabal O., Cataldi A. A., Bigi F.(2008). Study of the role of Mce3R on the transcription of mce genes of Mycobacterium tuberculosis. BMC Microbiol 8, 38. [View Article][PubMed] [Google Scholar]
  30. Via L. E., Lin P. L., Ray S. M., Carrillo J., Allen S. S., Eum S. Y., Taylor K., Klein E., Manjunatha U.& other authors (2008). Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates. Infect Immun 76, 23332340. [View Article][PubMed] [Google Scholar]
  31. Vindal V., Ranjan S., Ranjan A.(2007a). In silico analysis and characterization of GntR family of regulators from Mycobacterium tuberculosis. Tuberculosis (Edinb) 87, 242247. [View Article][PubMed] [Google Scholar]
  32. Vindal V., Suma K., Ranjan A.(2007b). GntR family of regulators in Mycobacterium smegmatis: a sequence and structure based characterization. BMC Genomics 8, 289. [View Article][PubMed] [Google Scholar]
  33. Voskuil M. I., Schnappinger D., Visconti K. C., Harrell M. I., Dolganov G. M., Sherman D. R., Schoolnik G. K.(2003). Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med 198, 705713. [View Article][PubMed] [Google Scholar]
  34. Wayne L. G., Sohaskey C. D.(2001). Nonreplicating persistence of Mycobacterium tuberculosis. Annu Rev Microbiol 55, 139163. [View Article][PubMed] [Google Scholar]

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error