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Volume 157, Issue 3

Induction of cell death after localization to the host cell mitochondria by the PE_PGRS33 protein Free

Abstract

PE_PGRS33 is the most studied member of the unique PE family of mycobacterial proteins. These proteins are composed of a PE domain (Pro–Glu motif), a linker region and a PGRS domain (polymorphic GC-rich-repetitive sequence). Previous studies have shown that PE_PGRS33 is surface-exposed, constitutively expressed during growth and infection, involved in creating antigenic diversity, and able to induce death in transfected or infected eukaryotic cells. In this study, we showed that PE_PGRS33 co-localizes to the mitochondria of transfected cells, a phenomenon dependent on the linker region and the PGRS domain, but not the PE domain. Using different genetic fusions and chimeras, we also demonstrated a direct correlation between localization to the host mitochondria and the induction of cell death. Finally, although all constructs localizing to the mitochondria did induce apoptosis, only the wild-type PE_PGRS33 with its own PE domain also induced primary necrosis, indicating a potentially important role for the PE domain. Considering the importance of primary necrosis in dissemination during natural infection, the PE_PGRS33 protein may play a crucial role in the pathogenesis of tuberculosis.

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  • Accepted:
  • Revised:
  • Published Online:
Keyword(s): BMMO, bone marrow-derived macrophages , IFA, immunofluorescence assay , mAb, monoclonal antibody , PI, propidium iodide and RD, human rhabdomyosarcoma
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2011-03-01
2024-04-18
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References

  1. Abarca-Rojano, E., Rosas-Medina, P., Zamudio-Cortéz, P., Mondragón-Flores, R. & Sánchez-Garcia, F. J. 2003; Mycobacterium tuberculosis virulence correlates with mitochondrial cytochrome c release in infected macrophages. Scand J Immunol 58:419–427
     [Google Scholar]
  2. Abdallah A. M., Verboom T., Hannes F., Safi M., Strong M., Eisenberg D., Musters R. J., Vandenbroucke-Grauls C. M., Applemelk B. J. other authors 2006; A specific secretion system mediates PPE41 transport in pathogenic mycobacteria. Mol Microbiol 62:667–679
     [Google Scholar]
  3. Abdallah A. M., Gey van Pittius N. C., Champion P. A. D., Cox J., Luirink J., Vandenbroucke-Grauls C. M., Applemelk B. J., Bitter W. 2007; Type VII secretion – mycobacteria show the way. Nat Rev Microbiol 5:883–891
     [Google Scholar]
  4. Abdallah A. M., Verboom T., Weerdenburg E. M., Gey van Pittius N. C., Mahasha P. W., Jiménez C., Parra M., Cadieux N., Brennan M. J. other authors 2009; PPE and PE_PGRS proteins of Mycobacterium marinum are transported via the type VII secretion system ESX-5. Mol Microbiol 73:329–340
     [Google Scholar]
  5. Balaji K. N., Goyal G., Narayana Y., Srinivas M., Chaturvedi R., Mohammad S. 2007; Apoptosis triggered by Rv1818c, a PE family gene from Mycobacterium tuberculosis is regulated by mitochondrial intermediates in T cells. Microbes Infect 9:271–281
     [Google Scholar]
  6. Basu S., Pathak S. K., Banerjee A., Pathak S., Bhattacharyya A., Yang Z., Talarico S., Kundu M., Basu J. 2007; Execution of macrophage apoptosis by PE_PGRS33 of Mycobacterium tuberculosis is mediated by Toll-like receptor 2-dependent release of tumor necrosis factor- α . J Biol Chem 282:1039–1050
     [Google Scholar]
  7. Brennan M. J., Delogu G. 2002; The PE multigene family: a ‘molecular mantra’ for mycobacteria. Trends Microbiol 10:246–249
     [Google Scholar]
  8. Brennan M. J., Delogu G., Chen Y., Bardarov S., Kriakov J., Alavi M., Jacobs W. R. 2001; Evidence that mycobacterial PE_PGRS proteins are cell surface constituents that influence interactions with other cells. Infect Immun 69:7326–7333
     [Google Scholar]
  9. Brennan M. J., Gey van Pittius N. C., Espitia C. 2005; The PE and PPE multigene families of Mycobacteria. In Tuberculosis and the Tubercle Bacillus pp 513–525 Edited by Cole S. T., Eisenach K. D., McMurray D. N., Jacobs W. R. Washington, DC: American Society for Microbiology;
     [Google Scholar]
  10. Cadieux N., Kadner R. J. 1999; Site-directed disulfide bonding reveals an interaction site between energy-coupling protein TonB and BtuB, the outer membrane cobalamin transporter. Proc Natl Acad Sci U S A 96:10673–10678
     [Google Scholar]
  11. Camus J. C., Pryor M., Médigue C., Cole S. T. 2002; Re-annotation of the genome sequence of Mycobacterium tuberculosis H37Rv. Microbiology 148:2967–2973
     [Google Scholar]
  12. Chen M., Gan H., Remold H. G. 2006; A mechanism of virulence: virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis. J Immunol 176:3707–3716
     [Google Scholar]
  13. 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 393:537–544
     [Google Scholar]
  14. Delogu G., Pusceddu C., Bua A., Fadda G., Brennan M. J., Zanetti S. 2004; Rv1818c-encoded PE_PGRS protein of Mycobacterium tuberculosis is surface exposed and influences bacterial cell structure. Mol Microbiol 52:725–733
     [Google Scholar]
  15. Delogu G., Sanguinetti M., Pusceddu C., Bua A., Brennan M. J., Zanetti S., Fadda G. 2006; PE_PGRS proteins are differentially expressed by Mycobacterium tuberculosis in host tissues. Microbes Infect 8:2061–2067
     [Google Scholar]
  16. Dheenadhayalan V., Delogu G., Brennan M. J. 2006a; Expression of the PE_PGRS33 protein in Mycobacterium smegmatis triggers necrosis in macrophages and enhanced mycobacterial survival. Microbes Infect 8:262–272
     [Google Scholar]
  17. Dheenadhayalan V., Delogu G., Sanguinetti M., Fadda G., Brennan M. J. 2006b; Variable expression patterns of Mycobacterium tuberculosis PE_PGRS genes: evidence that PE_PGRS16 and PE_PGRS26 are inversely regulated in vivo. J Bacteriol 188:3721–3725
     [Google Scholar]
  18. Duan L., Gan H., Golan D. E., Remold H. G. 2002; Critical role of mitochondrial damage in determining outcome of macrophage infection with Mycobacterium tuberculosis . J Immunol 169:5181–5187
     [Google Scholar]
  19. Espitia C., Laclette J. P., Mondragón-Palomino M., Amador A., Campuzano J., Martens A., Singh M., Cicero R., Zhang Y., Moreno C. 1999; The PE-PGRS glycine-rich proteins of Mycobacterium tuberculosis : a new family of fibronectin-binding proteins?. Microbiology 145:3487–3495
     [Google Scholar]
  20. Flores J., Espitia C. 2003; Differential expression of PE and PE_PGRS genes in Mycobacterium tuberculosis strains. Gene 318:75–81
     [Google Scholar]
  21. Fratazzi C., Arbeit R. D., Carini C., Remold H. G. 1997; Programmed cell death of Mycobacterium avium serovar 4-infected human macrophages prevents the Mycobacteria from spreading and induces mycobacterial growth inhibition by freshly added, uninfected macrophages. J Immunol 158:4320–4327
     [Google Scholar]
  22. Gan H., He X., Duan L., Mirabile-Levens E., Kornfeld H., Remold H. G. 2005; Enhancement of antimicrobial activity of macrophages by stabilization of inner mitochondrial membrane potential. J Infect Dis 191:1292–1300
     [Google Scholar]
  23. Gey van Pittius N. C., Sampson S. L., Lee H., Kim Y., van Helden P. D., Warren R. M. 2006; Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions. BMC Evol Biol 6:95
     [Google Scholar]
  24. Golstein P., Kroemer G. 2007; Cell death by necrosis: toward a molecular definition. Trends Biochem Sci 32:37–43
     [Google Scholar]
  25. Gordon S. V., Eiglmeier K., Brosch R., Garnier T., Honoré N., Barrell B., Cole S. T. 1999; Genomics of Mycobacterium tuberculosis and Mycobacterium leprae . In Mycobacteria: molecular biology and virulence pp 93–109 Edited by Ratledge C., Dale J. Oxford: Blackwell Science Ltd;
     [Google Scholar]
  26. Hillion J. A., Takahashi K., Maric D., Ruetzler C., Barker L. J., Hallenbeck M. 2005; Development of an ischemic tolerance model in a PC12 cell line. J Cereb Blood Flow Metab 25:154–162
     [Google Scholar]
  27. Karboul A., Mazza A., Gey van Pittius N. C., Ho J. L., Brousseau R., Mardassi H. 2008; Frequent homologous recombination events in Mycobacterium tuberculosis PE/PPE multigene families: potential role in antigenic variability. J Bacteriol 190:7838–7846
     [Google Scholar]
  28. Kozjak-Pavlovic V., Ross K., Rudel T. 2008; Import of bacterial pathogenicity factors into mitochondria. Curr Opin Microbiol 11:9–14
     [Google Scholar]
  29. McDonough K. A., Kress Y., Bloom B. R. 1993; Pathogenesis of tuberculosis: interactions of Mycobacterium tuberculosis with macrophages. Infect Immun 61:2763–2773
     [Google Scholar]
  30. Müller A., Rassow J., Grimm J., Machuy N., Meyer T. F., Rudel T. 2002; VDAC and the bacterial porin PorB of Neisseria gonorrhoeae share mitochondrial import pathways. EMBO J 21:1916–1929
     [Google Scholar]
  31. Nougayrède J.-P., Donnenberg M. S. 2004; Enteropathogenic Escherichia coli EspF is targeted to mitochondria and is required to initiate the mitochondrial death pathway. Cell Microbiol 6:1097–1111
     [Google Scholar]
  32. Papatheodorou P., Domańska G., Öxle M., Mathieu J., Selchow O., Kenny B., Rassow J. 2006; The enteropathogenic Escherichia coli (EPEC) Map effector is imported into the mitochondrial matrix by the TOM/Hsp70 system and alters organelle morphology. Cell Microbiol 8:677–689
     [Google Scholar]
  33. Park J. S., Tamayo M. H., Gonzalez-Juarrero M., Orme I. M., Ordway D. J. 2006; Virulent clinical isolates of Mycobacterium tuberculosis grow rapidly and induce cellular necrosis but minimal apoptosis in murine macrophages. J Leukoc Biol 79:80–86
     [Google Scholar]
  34. Parra M., Cadieux N., Pickett T., Dheenadhayalan V., Brennan M. J. 2006; A PE protein expressed by Mycobacterium avium is an effective T-cell immunogen. Infect Immun 74:786–789
     [Google Scholar]
  35. Porcelli S. A., Jacobs W. R. Jr 2008; Tuberculosis: unsealing the apoptotic envelope. Nat Immunol 9:1101–1102
     [Google Scholar]
  36. Poulet S., Cole S. T. 1995; Characterization of the highly abundant polymorphic GC-rich-repetitive sequence (PGRS) present in Mycobacterium tuberculosis . Arch Microbiol 163:87–95
     [Google Scholar]
  37. Ramakrishnan L., Federspiel N. A., Falkow S. 2000; Granuloma-specific expression of Mycobacterium virulence proteins from the glycine-rich PE-PGRS family. Science 288:1436–1439
     [Google Scholar]
  38. Schaible U. E., Winau F., Sieling P. A., Fischer K., Collins H. L., Hagens K., Modlin R. L., Brinkmann V., Kaufmann S. H. 2003; Apoptosis facilitates antigen presentation to T lymphocytes through MCH-I and CD1 in tuberculosis. Nat Med 9:1039–1046
     [Google Scholar]
  39. Singh P. P., Parra M., Cadieux N., Brennan M. J. 2008; A comparative study of host response to three Mycobacterium tuberculosis PE_PGRS proteins. Microbiology 154:3469–3479
     [Google Scholar]
  40. Stamm L. M., Morisaki J. H., Gao L. Y., Jeng R. L., McDonald K. L., Roth R., Takeshita S., Heuser J., Welch M. D., Brown E. J. 2003; Mycobacterium marinum escapes from phagosomes and is propelled by actin-based motility. J Exp Med 198:1361–1368
     [Google Scholar]
  41. Talaat A. M., Lyons M. R., Howard S. T., Johnston S. A. 2004; The temporal expression profile of Mycobacterium tuberculosis infection in mice. Proc Natl Acad Sci U S A 101:4602–4607
     [Google Scholar]
  42. Talarico S., Cave M. D., Marrs C. F., Foxman B., Zhang L., Yang Z. 2005; Variation of the Mycobacterium tuberculosis PE_PGRS33 gene among clinical isolates. J Clin Microbiol 43:4954–4960
     [Google Scholar]
  43. Talarico S., Cave M. D., Foxman B., Marrs C. F., Zhang L., Bates J. H., Yang Z. 2007; Association of Mycobacterium tuberculosis PE_PGRS33 polymorphism with clinical and epidemiological characteristics. Tuberculosis (Edinb 87:338–346
     [Google Scholar]
  44. Talarico S., Zhang L., Marrs C. F., Foxman B., Cave M. D., Brennan M. J., Yang Z. 2008; Mycobacterium tuberculosis PE_PGRS16 and PE_PGRS26 genetic polymorphism among clinical isolates. Tuberculosis (Edinb 88:283–294
     [Google Scholar]
  45. Towbin H., Staehlin T., Gordon J. 1979; Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A 76:4350–4354
     [Google Scholar]
  46. van der Wel N., Hava D., Houben D., Fluitsma D., van Zon M., Pierson J., Brenner M. P., Peters J. 2007; M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cell. Cell 129:1287–1298
     [Google Scholar]
  47. WHO 2008; Global tuberculosis control - surveillance, planning, financing. In World Health Organization report Geneva: World Health Organization;
     [Google Scholar]
  48. Yuan Z., Mattick J. S., Teasdale R. D. 2004; SVMtm: support vector machines to predict transmembrane segments. J Comput Chem 25:632–636
     [Google Scholar]
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Induction of cell death after localization to the host cell mitochondria by the Mycobacterium tuberculosis PE_PGRS33 protein
Microbiology 157, 793 (2011); https://doi.org/10.1099/mic.0.041996-0
/content/journal/micro/10.1099/mic.0.041996-0
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