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Eukaryotic Cell, October 2009, p. 1511-1520, Vol. 8, No. 10
1535-9778/09/$08.00+0     doi:10.1128/EC.00166-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Role of Ferroxidases in Iron Uptake and Virulence of Cryptococcus neoformans{triangledown} ,{dagger}

Won Hee Jung,1 Guanggan Hu,2 Wayne Kuo,2 and James W. Kronstad2*

Department of Biotechnology, Chung-Ang University, 72-1 Naeri, Deaduck, Ansung, 456-756, Kyunggi, Republic of Korea,1 The Michael Smith Laboratories, Department of Microbiology and Immunology, and Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada2

Received 11 June 2009/ Accepted 11 August 2009

Iron acquisition is a critical aspect of the virulence of many pathogenic microbes, and iron limitation is an important defense mechanism for mammalian hosts. We are examining mechanisms of iron regulation and acquisition in the fungal pathogen Cryptococcus neoformans, and here, we characterize the roles of the ferroxidases Cfo1 and Cfo2. Cfo1 is required for the reductive iron uptake system that mediates the utilization of transferrin, an important iron source for C. neoformans during infection. The virulence of a cfo1 mutant was attenuated in a mouse model of cryptococcosis, and the mutant also displayed increased sensitivities to the antifungal drugs fluconazole and amphotericin B. Wild-type levels of drug sensitivity were restored by the addition of exogenous heme, which suggested that reduced levels of intracellular iron may curtail heme levels and interfere with ergosterol biosynthesis. We constructed green fluorescent protein (GFP) fusion proteins and found elevated expression of Cfo1-GFP upon iron limitation, as well as localization of the fusion to the plasma membrane. Trafficking to this location was disrupted by a defect in the catalytic subunit of cyclic AMP-dependent protein kinase. This result is consistent with findings from studies indicating an influence of the kinase on the expression of protein-trafficking functions in C. neoformans.

* Corresponding author. Mailing address: The Michael Smith Laboratories, Department of Microbiology and Immunology, and Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada. Phone: (604) 822-4732. Fax: (604) 822-2114. E-mail: kronstad{at}interchange.ubc.ca

{triangledown} Published ahead of print on 21 August 2009.

{dagger} Supplemental material for this article may be found at http://ec.asm.org/.

Eukaryotic Cell, October 2009, p. 1511-1520, Vol. 8, No. 10
1535-9778/09/$08.00+0     doi:10.1128/EC.00166-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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