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References

  1. Askwith, C., D. Eide, A. Van Ho, P. S. Bernard, L. Li, S. Davis-Kaplan, et al. 1994. The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell 76: 403-410.
    CrossRef
  2. Choi, J., A. W. Vogl, and J. W. Kronstad. 2012. Regulated expression of cyclic AMP-dependent protein kinase A reveals an influence on cell size and the secretion of virulence factors in Cryptococcus neoformans. Mol. Microbiol. 85: 700-715.
    Pubmed CrossRef
  3. Dancis, A., D. S. Yuan, D. Haile, C. Askwith, D. Eide, C. Moehle, et al. 1994. Molecular characterization of a copper transport protein in S. cerevisiae: An unexpected role for copper in iron transport. Cell 76: 393-402.
    CrossRef
  4. Davidson, R. C., J. R. Blankenship, P. R. Kraus, M. de Jesus Berrios, C. M. Hull, C. D’Souza, et al. 2002. A PCR-based strategy to generate integrative targeting alleles with large regions of homology. Microbiology 148: 2607-2615.
    Pubmed
  5. Hentze, M. W., M. U. Muckenthaler, and N. C. Andrews. 2004. Balancing acts: Molecular control of mammalian iron metabolism. Cell 117: 285-297.
    CrossRef
  6. Howard, D. H. 1999. Acquisition, transport, and storage of iron by pathogenic fungi. Clin. Microbiol. Rev. 12: 394-404.
    Pubmed PMC
  7. Ibrahim, A. S., J. E. Edwards Jr., Y. Fu, and B. Spellberg. 2006. Deferiprone iron chelation as a novel therapy for experimental mucormycosis. J. Antimicrob. Chemother. 58: 1070-1073.
    Pubmed CrossRef
  8. Jacobson, E. S., A. P. Goodner, and K. J. Nyhus. 1998. Ferrous iron uptake in Cryptococcus neoformans. Infect. Immun. 66:4169-4175.
    Pubmed PMC
  9. Jung, W. H., G. Hu, W. Kuo, and J. W. Kronstad. 2009. Role of ferroxidases in iron uptake and virulence of Cryptococcus neoformans. Eukaryot. Cell 8: 1511-1520.
    Pubmed PMC CrossRef
  10. Jung, W. H. and J. W. Kronstad. 2008. Iron and fungal pathogenesis: A case study with Cryptococcus neoformans Cell. Microbiol. 10: 277-284.
    Pubmed CrossRef
  11. Jung, W. H., S. Saikia, G. Hu, J. Wang, C. K. Fung, C. D’Souza, et al. 2010. HapX positively and negatively regulates the transcriptional response to iron deprivation in Cryptococcus neoformans. PLoS Pathog. 6: e1001209.
    Pubmed PMC CrossRef
  12. Jung, W. H., A. Sham, T. Lian, A. Singh, D. J. Kosman, and J. W. Kronstad. 2008. Iron source preference and regulation of iron uptake in Cryptococcus neoformans. PLoS Pathog. 4: e45.
    Pubmed PMC CrossRef
  13. Jung, W. H., A. Sham, R. White, and J. W. Kronstad. 2006. Iron regulation of the major virulence factors in the AIDSassociated pathogen Cryptococcus neoformans. PLoS Biol. 4:e410.
    Pubmed PMC CrossRef
  14. Kronstad, J., S. Saikia, E. D. Nielson, M. Kretschmer, W. Jung, G. Hu, et al. 2012. Adaptation of Cryptococcus neoformans to mammalian hosts: Integrated regulation of metabolism and virulence. Eukaryot. Cell 11: 109-118.
    Pubmed PMC CrossRef
  15. Kronstad, J. W., R. Attarian, B. Cadieux, J. Choi, C. A. D'Souza, E. J. Griffiths, et al. 2011. Expanding fungal pathogenesis:Cryptococcus breaks out of the opportunistic box. Nat. Rev. Microbiol. 9: 193-203.
    Pubmed CrossRef
  16. Levitz, S. M., S. H. Nong, K. F. Seetoo, T. S. Harrison, R. A. Speizer, and E. R. Simons. 1999. Cryptococcus neoformans resides in an acidic phagolysosome of human macrophages. Infect. Immun. 67: 885-890.
    Pubmed PMC
  17. Livak, K. J. and T. D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402-408.
  18. Nyhus, K. J., A. T. Wilborn, and E. S. Jacobson. 1997. Ferric iron reduction by Cryptococcus neoformans. Infect. Immun. 65:434-438.
    Pubmed PMC
  19. Perfect, J. R., N. Ketabchi, G. M. Cox, C. W. Ingram, and C. L. Beiser. 1993. Karyotyping of Cryptococcus neoformans as an epidemiological tool. J. Clin. Microbiol. 31: 3305-3309.
    Pubmed PMC
  20. Severance, S., S. Chakraborty, and D. J. Kosman. 2004. The Ftr1p iron permease in the yeast plasma membrane: Orientation, topology and structure-function relationships. Biochem. J. 380:487-496.
    Pubmed PMC CrossRef
  21. Stearman, R., D. S. Yuan, Y. Yamaguchi-Iwai, R. D. Klausner, and A. Dancis. 1996. A permease-oxidase complex involved in high-affinity iron uptake in yeast. Science 271: 1552-1557.
    Pubmed CrossRef
  22. Tangen, K. L., W. H. Jung, A. P. Sham, T. Lian, and J. W. Kronstad. 2007. The iron- and cAMP-regulated gene SIT1 influences ferrioxamine B utilization, melanization and cell wall structure in Cryptococcus neoformans. Microbiology 153: 29-41.
    Pubmed CrossRef
  23. Wang, J. and K. Pantopoulos. 2011. Regulation of cellular iron metabolism. Biochem. J. 434: 365-381.
    Pubmed PMC CrossRef
  24. Yu, J. H., Z. Hamari, K. H. Han, J. A. Seo, Y. ReyesDominguez, and C. Scazzocchio. 2004. Double-joint PCR: A PCR-based molecular tool for gene manipulations in filamentous fungi. Fungal Genet. Biol. 41: 973-981.
    Pubmed CrossRef

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Article

Research article

J. Microbiol. Biotechnol. 2012; 22(12): 1644-1652

Published online December 28, 2012 https://doi.org/10.4014/jmb.1209.09019

Copyright © The Korean Society for Microbiology and Biotechnology.

A Human Fungal Pathogen Cryptococcus neoformans Expresses Three Distinct Iron Permease Homologs

Kyunghwan Han 1, Eunsoo Do 1 and Won Hee Jung 1*

Department of Biotechnology, Chung-Ang University, Anseong 456-756, Korea

Received: September 6, 2012; Accepted: September 10, 2012

Abstract

Iron plays a key role in host-pathogen interactions.
Microbial pathogens require iron for survival and virulence,
whereas mammalian hosts sequester and withhold iron as
a means of nutritional immunity. We previously identified
two paralogous genes, CFT1 and CFT2, which encode
homologs of a fungal iron permease, Cft1 and Cft2,
respectively, in the human fungal pathogen Cryptococcus
neoformans. Cft1 was shown to play a role in the highaffinity
reductive iron uptake system, and was required
for transferrin utilization and full virulence in mammalian
hosts. However, no role of Cft2 has been suggested yet.
Here, we identified the third gene, CFT3, that produces an
additional fungal iron permease homolog in C. neoformans,
and we also generated the cft3 mutant for functional
characterization. We aimed to reveal distinct functions of
Cft1, Cft2 and Cft3 by analyzing phenotypes of the
mutants lacking CFT1, CFT2 and CFT3, respectively. The
endogenous promoter of CFT1, CFT2 and CFT3 was
replaced with the inducible GAL7 promoter in the wildtype
strain or in the cft1 mutant for gain-of-function
analysis. Using these strains, we were able to find that
CFT2 is required for growth in low-iron conditions in the
absence of CFT1 and that overexpression of CFT2
compensates for deficiency of the cft1 mutant in iron
uptake and various cellular stress conditions. However,
unlike CFT2, no clear phenotypic characteristic of the cft3
mutant and the strain overexpressing CFT3 was observed.
Overall, our data suggested a redundant role of Cft2
in the high-affinity iron uptake and stress responses in
C. neoformans.

Keywords: Fungal pathogen, C. neoformans, iron uptake, iron permease

References

  1. Askwith, C., D. Eide, A. Van Ho, P. S. Bernard, L. Li, S. Davis-Kaplan, et al. 1994. The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell 76: 403-410.
    CrossRef
  2. Choi, J., A. W. Vogl, and J. W. Kronstad. 2012. Regulated expression of cyclic AMP-dependent protein kinase A reveals an influence on cell size and the secretion of virulence factors in Cryptococcus neoformans. Mol. Microbiol. 85: 700-715.
    Pubmed CrossRef
  3. Dancis, A., D. S. Yuan, D. Haile, C. Askwith, D. Eide, C. Moehle, et al. 1994. Molecular characterization of a copper transport protein in S. cerevisiae: An unexpected role for copper in iron transport. Cell 76: 393-402.
    CrossRef
  4. Davidson, R. C., J. R. Blankenship, P. R. Kraus, M. de Jesus Berrios, C. M. Hull, C. D’Souza, et al. 2002. A PCR-based strategy to generate integrative targeting alleles with large regions of homology. Microbiology 148: 2607-2615.
    Pubmed
  5. Hentze, M. W., M. U. Muckenthaler, and N. C. Andrews. 2004. Balancing acts: Molecular control of mammalian iron metabolism. Cell 117: 285-297.
    CrossRef
  6. Howard, D. H. 1999. Acquisition, transport, and storage of iron by pathogenic fungi. Clin. Microbiol. Rev. 12: 394-404.
    Pubmed KoreaMed
  7. Ibrahim, A. S., J. E. Edwards Jr., Y. Fu, and B. Spellberg. 2006. Deferiprone iron chelation as a novel therapy for experimental mucormycosis. J. Antimicrob. Chemother. 58: 1070-1073.
    Pubmed CrossRef
  8. Jacobson, E. S., A. P. Goodner, and K. J. Nyhus. 1998. Ferrous iron uptake in Cryptococcus neoformans. Infect. Immun. 66:4169-4175.
    Pubmed KoreaMed
  9. Jung, W. H., G. Hu, W. Kuo, and J. W. Kronstad. 2009. Role of ferroxidases in iron uptake and virulence of Cryptococcus neoformans. Eukaryot. Cell 8: 1511-1520.
    Pubmed KoreaMed CrossRef
  10. Jung, W. H. and J. W. Kronstad. 2008. Iron and fungal pathogenesis: A case study with Cryptococcus neoformans Cell. Microbiol. 10: 277-284.
    Pubmed CrossRef
  11. Jung, W. H., S. Saikia, G. Hu, J. Wang, C. K. Fung, C. D’Souza, et al. 2010. HapX positively and negatively regulates the transcriptional response to iron deprivation in Cryptococcus neoformans. PLoS Pathog. 6: e1001209.
    Pubmed KoreaMed CrossRef
  12. Jung, W. H., A. Sham, T. Lian, A. Singh, D. J. Kosman, and J. W. Kronstad. 2008. Iron source preference and regulation of iron uptake in Cryptococcus neoformans. PLoS Pathog. 4: e45.
    Pubmed KoreaMed CrossRef
  13. Jung, W. H., A. Sham, R. White, and J. W. Kronstad. 2006. Iron regulation of the major virulence factors in the AIDSassociated pathogen Cryptococcus neoformans. PLoS Biol. 4:e410.
    Pubmed KoreaMed CrossRef
  14. Kronstad, J., S. Saikia, E. D. Nielson, M. Kretschmer, W. Jung, G. Hu, et al. 2012. Adaptation of Cryptococcus neoformans to mammalian hosts: Integrated regulation of metabolism and virulence. Eukaryot. Cell 11: 109-118.
    Pubmed KoreaMed CrossRef
  15. Kronstad, J. W., R. Attarian, B. Cadieux, J. Choi, C. A. D'Souza, E. J. Griffiths, et al. 2011. Expanding fungal pathogenesis:Cryptococcus breaks out of the opportunistic box. Nat. Rev. Microbiol. 9: 193-203.
    Pubmed CrossRef
  16. Levitz, S. M., S. H. Nong, K. F. Seetoo, T. S. Harrison, R. A. Speizer, and E. R. Simons. 1999. Cryptococcus neoformans resides in an acidic phagolysosome of human macrophages. Infect. Immun. 67: 885-890.
    Pubmed KoreaMed
  17. Livak, K. J. and T. D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402-408.
  18. Nyhus, K. J., A. T. Wilborn, and E. S. Jacobson. 1997. Ferric iron reduction by Cryptococcus neoformans. Infect. Immun. 65:434-438.
    Pubmed KoreaMed
  19. Perfect, J. R., N. Ketabchi, G. M. Cox, C. W. Ingram, and C. L. Beiser. 1993. Karyotyping of Cryptococcus neoformans as an epidemiological tool. J. Clin. Microbiol. 31: 3305-3309.
    Pubmed KoreaMed
  20. Severance, S., S. Chakraborty, and D. J. Kosman. 2004. The Ftr1p iron permease in the yeast plasma membrane: Orientation, topology and structure-function relationships. Biochem. J. 380:487-496.
    Pubmed KoreaMed CrossRef
  21. Stearman, R., D. S. Yuan, Y. Yamaguchi-Iwai, R. D. Klausner, and A. Dancis. 1996. A permease-oxidase complex involved in high-affinity iron uptake in yeast. Science 271: 1552-1557.
    Pubmed CrossRef
  22. Tangen, K. L., W. H. Jung, A. P. Sham, T. Lian, and J. W. Kronstad. 2007. The iron- and cAMP-regulated gene SIT1 influences ferrioxamine B utilization, melanization and cell wall structure in Cryptococcus neoformans. Microbiology 153: 29-41.
    Pubmed CrossRef
  23. Wang, J. and K. Pantopoulos. 2011. Regulation of cellular iron metabolism. Biochem. J. 434: 365-381.
    Pubmed KoreaMed CrossRef
  24. Yu, J. H., Z. Hamari, K. H. Han, J. A. Seo, Y. ReyesDominguez, and C. Scazzocchio. 2004. Double-joint PCR: A PCR-based molecular tool for gene manipulations in filamentous fungi. Fungal Genet. Biol. 41: 973-981.
    Pubmed CrossRef