Genetic system underlying responses of Cryptococcus neoformans to cadmium

Cryptococcus neoformans, basidiomycetous pathogenic yeast, is basically an environmental fungus and, therefore, challenged by ever changing environments. In this study, we focused on how C. neoformans responds to stress caused by cadmium that is one of high-risk pollutants. By tracking phenotypes of the resistance or sensitivity to cadmium, we undertook forward and reverse genetic studies to identify genes involved in cadmium metabolism in C. neoformans. We found that the main route of Cd²⁺ influx is through Mn²⁺ ion transporter, Smf1, which is an ortholog of Nramp (natural resistance-associated macrophage protein 1) of mouse. We found that serotype A strains are generally more resistant to cadmium than serotype D strains and that cadmium resistance of H99, a representative of serotype A strains, was found to be due to a partial defect in SMF1. We found that calcium channel has a subsidiary role for cadmium uptake. We also showed that Pca1 (P-type-ATPase) functions as an extrusion pump for cadmium. We examined the effects of some metals on cadmium toxicity and suggested (i) that Ca²⁺ and Zn²⁺ could exert their protective function against Cd²⁺ via restoring cadmium-inhibited cellular processes and (ii) that Mg²⁺ and Mn²⁺ could have antagonistic roles in an unknown Smf1-independent Cd²⁺ uptake system. We proposed a model for Cd2⁺-response of C. neoformans, which will serve as a platform for understanding how this organism copes with the toxic metal.