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Characterization of an iron permease in Cryptococcus neoformans Simmer, Megan Irene

Abstract

Cryptococcus neoformans is an opportunistic fungal pathogen with worldwide distribution. Pathogenesis is mediated by several virulence factors including growth at 37°C, melanin synthesis and capsule formation. Expression of the thick polysaccharide capsule is stimulated under iron-limiting conditions. Analysis of SAGE libraries of cells grown under iron-replete and iron-limited conditions identified orthologs of two components of the Saccharomyces cerevisiae high affinity iron uptake system, FTR1 and FET3. These genes, encoding the high affinity iron permease (FTR1) and the multicopper oxidase (FET3), form a cluster of functionally related genes in C. neoformans. Molecular genetic techniques were used to analyze the regulation of expression of FTR1 and FET3 by iron, copper and components of the PKA pathway. The results suggest that iron starvation stimulates transcription ofFTRl and FET3 regardless of genetic background and that maintenance of basal transcription of FTR1 requires the activity of P KA catalytic subunits. Supplemental copper stimulates FET3 expression but represses FTR1 expression. The contribution oiFTRl to C. neoformans growth under iron-limited conditions and response to oxidative stress was investigated in ftrl mutants. The results suggest that FTR1 is important for growth under iron-limiting conditions and that response to oxidative stress is also iron-dependent. The high-affinity iron transport system of C. neoformans represents a key cellular strategy for acquisition of a limiting nutrient in the environment. Elucidation of the mechanisms by which C. neoformans obtains iron under iron-limited conditions aids understanding of cell growth and proliferation inside the host and its potential contribution to virulence.

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