DOI QR코드

DOI QR Code

Mitochondrial Protein Nfu1 Influences Homeostasis of Essential Metals in the Human Fungal Pathogen Cryptococcus neoformans

  • Kim, Jeongmi (Department of Systems Biotechnology, Chung-Ang University) ;
  • Park, Minji (Department of Systems Biotechnology, Chung-Ang University) ;
  • Do, Eunsoo (Department of Systems Biotechnology, Chung-Ang University) ;
  • Jung, Won Hee (Department of Systems Biotechnology, Chung-Ang University)
  • Received : 2014.10.28
  • Accepted : 2014.11.20
  • Published : 2014.12.31

Abstract

Mitochondrial protein Nfu1 plays an important role in the assembly of mitochondrial Fe-S clusters and intracellular iron homeostasis in the model yeast Saccharomyces cerevisiae. In this study, we identified the Nfu1 ortholog in the human fungal pathogen Cryptococcus neoformans. Our data showed that C. neoformans Nfu1 localized in the mitochondria and influenced homeostasis of essential metals such as iron, copper and manganese. Marked growth defects were observed in the mutant lacking NFU1, which suggests a critical role of Nfu1 in Fe-S cluster biosynthesis and intracellular metal homeostasis in C. neoformans.

Keywords

References

  1. Zheng L, Cash VL, Flint DH, Dean DR. Assembly of ironsulfur clusters: identification of an iscSUA-hscBA-fdx gene cluster from Azotobacter vinelandii. J Biol Chem 1998;273: 13264-72. https://doi.org/10.1074/jbc.273.21.13264
  2. Frazzon J, Dean DR. Biosynthesis of the nitrogenase ironmolybdenum- cofactor from Azotobacter vinelandii. Met Ions Biol Syst 2002;39:163-86.
  3. Rees DC, Howard JB. Nitrogenase: standing at the crossroads. Curr Opin Chem Biol 2000;4:559-66. https://doi.org/10.1016/S1367-5931(00)00132-0
  4. Lill R, Dutkiewicz R, Elsasser HP, Hausmann A, Netz DJ, Pierik AJ, Stehling O, Urzica E, Muhlenhoff U. Mechanisms of iron-sulfur protein maturation in mitochondria, cytosol and nucleus of eukaryotes. Biochim Biophys Acta 2006;1763: 652-67. https://doi.org/10.1016/j.bbamcr.2006.05.011
  5. Runyen-Janecky L, Daugherty A, Lloyd B, Wellington C, Eskandarian H, Sagransky M. Role and regulation of ironsulfur cluster biosynthesis genes in Shigella flexneri virulence. Infect Immun 2008;76:1083-92. https://doi.org/10.1128/IAI.01211-07
  6. Rincon-Enriquez G, Crete P, Barras F, Py B. Biogenesis of Fe/S proteins and pathogenicity: IscR plays a key role in allowing Erwinia chrysanthemi to adapt to hostile conditions. Mol Microbiol 2008;67:1257-73. https://doi.org/10.1111/j.1365-2958.2008.06118.x
  7. Schrettl M, Beckmann N, Varga J, Heinekamp T, Jacobsen ID, Jochl C, Moussa TA, Wang S, Gsaller F, Blatzer M, et al. HapX-mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus. PLoS Pathog 2010;6: e1001124. https://doi.org/10.1371/journal.ppat.1001124
  8. Hsu PC, Yang CY, Lan CY. Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence. Eukaryot Cell 2011;10:207-25. https://doi.org/10.1128/EC.00158-10
  9. Jung WH, Saikia S, Hu G, Wang J, Fung CK, D'Souza C, White R, Kronstad JW. HapX positively and negatively regulates the transcriptional response to iron deprivation in Cryptococcus neoformans. PLoS Pathog 2010;6:e1001209. https://doi.org/10.1371/journal.ppat.1001209
  10. Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009;23:525-30. https://doi.org/10.1097/QAD.0b013e328322ffac
  11. Bartlett KH, Kidd SE, Kronstad JW. The emergence of Cryptococcus gattii in British Columbia and the Pacific Northwest. Curr Infect Dis Rep 2008;10:58-65. https://doi.org/10.1007/s11908-008-0011-1
  12. Kronstad J, Saikia S, Nielson ED, Kretschmer M, Jung W, Hu G, Geddes JM, Griffiths EJ, Choi J, Cadieux B, Caza M, Attarian R. Adaptation of Cryptococcus neoformans to mammalian hosts: integrated regulation of metabolism and virulence. Eukaryot Cell 2012;11:109-18. https://doi.org/10.1128/EC.05273-11
  13. Jung WH, Do E. Iron acquisition in the human fungal pathogen Cryptococcus neoformans. Curr Opin Microbiol 2013;16:686-91. https://doi.org/10.1016/j.mib.2013.07.008
  14. Jung WH, Sham A, White R, Kronstad JW. Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans. PLoS Biol 2006;4:e410. https://doi.org/10.1371/journal.pbio.0040410
  15. Dos Santos PC, Johnson DC, Ragle BE, Unciuleac MC, Dean DR. Controlled expression of nif and isc iron-sulfur protein maturation components reveals target specificity and limited functional replacement between the two systems. J Bacteriol 2007;189:2854-62. https://doi.org/10.1128/JB.01734-06
  16. Schilke B, Voisine C, Beinert H, Craig E. Evidence for a conserved system for iron metabolism in the mitochondria of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 1999; 96:10206-11. https://doi.org/10.1073/pnas.96.18.10206
  17. Jacobson MR, Cash VL, Weiss MC, Laird NF, Newton WE, Dean DR. Biochemical and genetic analysis of the nifUSVWZM cluster from Azotobacter vinelandii. Mol Gen Genet 1989;219:49-57.
  18. Strain J, Lorenz CR, Bode J, Garland S, Smolen GA, Ta DT, Vickery LE, Culotta VC. Suppressors of superoxide dismutase (SOD1) deficiency in Saccharomyces cerevisiae: identification of proteins predicted to mediate iron-sulfur cluster assembly. J Biol Chem 1998;273:31138-44. https://doi.org/10.1074/jbc.273.47.31138
  19. Gregg C, Kyryakov P, Titorenko VI. Purification of mitochondria from yeast cells. J Vis Exp 2009;24:1417.
  20. Davidson RC, Blankenship JR, Kraus PR, de Jesus Berrios M, Hull CM, D'Souza C, Wang P, Heitman J. A PCR-based strategy to generate integrative targeting alleles with large regions of homology. Microbiology 2002;148(Pt 8):2607-15.
  21. Yu JH, Hamari Z, Han KH, Seo JA, Reyes-Dominguez Y, Scazzocchio C. Double-joint PCR: a PCR-based molecular tool for gene manipulations in filamentous fungi. Fungal Genet Biol 2004;41:973-81. https://doi.org/10.1016/j.fgb.2004.08.001
  22. Toffaletti DL, Rude TH, Johnston SA, Durack DT, Perfect JR. Gene transfer in Cryptococcus neoformans by use of biolistic delivery of DNA. J Bacteriol 1993;175:1405-11.
  23. Yasmin S, Abt B, Schrettl M, Moussa TA, Werner ER, Haas H. The interplay between iron and zinc metabolism in Aspergillus fumigatus. Fungal Genet Biol 2009;46:707-13. https://doi.org/10.1016/j.fgb.2009.05.003
  24. Harris ED. Iron-copper interactions: some new revelations. Nutr Rev 1994;52:311-5.
  25. Chang A, Fink GR. Metal ion metabolism: the copper-iron connection. Curr Biol 1994;4:532-3. https://doi.org/10.1016/S0960-9822(00)00116-0
  26. Shingu-Vazquez M, Traven A. Mitochondria and fungal pathogenesis: drug tolerance, virulence, and potential for antifungal therapy. Eukaryot Cell 2011;10:1376-83. https://doi.org/10.1128/EC.05184-11
  27. Narasipura SD, Chaturvedi V, Chaturvedi S. Characterization of Cryptococcus neoformans variety gattii SOD2 reveals distinct roles of the two superoxide dismutases in fungal biology and virulence. Mol Microbiol 2005;55:1782-800. https://doi.org/10.1111/j.1365-2958.2005.04503.x
  28. Ma H, Hagen F, Stekel DJ, Johnston SA, Sionov E, Falk R, Polacheck I, Boekhout T, May RC. The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation. Proc Natl Acad Sci U S A 2009;106:12980-5. https://doi.org/10.1073/pnas.0902963106