Vacuolar zinc transporter Zrc1 is required for detoxification of excess intracellular zinc in the human fungal pathogen Cryptococcus neoformans

Minsu Cho; Guanggan Hu; Mélissa Caza; Linda C. Horianopoulos; James W. Kronstad; Won Hee Jung

doi:10.1007/s12275-018-7475-y

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Vacuolar zinc transporter Zrc1 is required for detoxification of excess intracellular zinc in the human fungal pathogen Cryptococcus neoformans: Minsu Cho ¹, Guanggan Hu ², Mélissa Caza ², Linda C. Horianopoulos ², James W. Kronstad ², Won Hee Jung ¹; Journal of Microbiology 2018;56(1):65-71.
DOI: https://doi.org/10.1007/s12275-018-7475-y
Published online: January 4, 2018

¹Department of Systems Biotechnology, Chung-Ang University, Anseong 17546, Republic of Korea , ²Michael Smith Laboratories, University of British Columbia, Vancouver, B.C. V6T 1Z4, Canada¹Department of Systems Biotechnology, Chung-Ang University, Anseong 17546, Republic of Korea , ²Michael Smith Laboratories, University of British Columbia, Vancouver, B.C. V6T 1Z4, Canada

Corresponding author: Won Hee Jung , Tel: +82-31-670-3068,

Received: 6 November 2017 • Revised: 28 November 2017 • Accepted: 30 November 2017

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Abstract

Zinc is an important transition metal in all living organisms and is required for numerous biological processes. However, excess zinc can also be toxic to cells and cause cellular stress. In the model fungus Saccharomyces cerevisiae, a vacuolar zinc transporter, Zrc1, plays important roles in the storage and detoxification of excess intracellular zinc to protect the cell. In this study, we identified an ortholog of the S. cerevisiae ZRC1 gene in the human fungal pathogen Cryptococcus neoformans. Zrc1 was localized in the vacuolar membrane in C. neoformans, and a mutant lacking ZRC1 showed significant growth defects under high-zinc conditions. These results suggested a role for Zrc1 in zinc detoxification. However, contrary to our expectation, the expression of Zrc1 was induced in cells grown in zinc-limited conditions and decreased upon the addition of zinc. These expression patterns were similar to those of Zip1, the high-affinity zinc transporter in the plasma membrane of C. neoformans. Furthermore, we used the zrc1 mutant in a murine model of cryptococcosis to examine whether a mammalian host could inhibit the survival of C. neoformans using zinc toxicity. We found that the mutant showed no difference in virulence compared with the wildtype strain. This result suggests that Zrc1-mediated zinc detoxification is not required for the virulence of C. neoformans, and imply that zinc toxicity may not be an important aspect of the host immune response to the fungus.

Keywords: Cryptococcus neoformans;vacuole;virulence;zinc;Zrc1

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Vacuolar zinc transporter Zrc1 is required for detoxification of excess intracellular zinc in the human fungal pathogen Cryptococcus neoformans

J. Microbiol. 2018;56(1):65-71. Published online January 4, 2018

DOI: https://doi.org/10.1007/s12275-018-7475-y

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