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Mol Microbiol. 2018 Jun;108(5):473-494. doi: 10.1111/mmi.13960. Epub 2018 Apr 24.

Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans.

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Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Department of Biochemistry and Biophysics, UCSF, San Francisco, CA, USA.
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.


The ability of the human fungal pathogen Cryptococcus neoformans to adapt to variable copper (Cu) environments within the host is key for successful dissemination and colonization. During pulmonary infection, host alveolar macrophages compartmentalize Cu into the phagosome and C. neoformans Cu-detoxifying metallothioneins, MT1 and MT2, are required for survival of the pathogen. In contrast, during brain colonization the C. neoformans Cu+ importers Ctr1 and Ctr4 are required for virulence. Central for the regulation and expression of both the Cu detoxifying MT1/2 and the Cu acquisition Ctr1/4 proteins is the Cu-metalloregulatory transcription factor Cuf1, an established C. neoformans virulence factor. Due to the importance of the distinct C. neoformans Cu homeostasis mechanisms during host colonization and virulence, and to the central role of Cuf1 in regulating Cu homeostasis, we performed a combination of RNA-Seq and ChIP-Seq experiments to identify differentially transcribed genes between conditions of high and low Cu. We demonstrate that the transcriptional regulation exerted by Cuf1 is intrinsically complex and that Cuf1 also functions as a transcriptional repressor. The Cu- and Cuf1-dependent regulon in C. neoformans reveals new adaptive mechanisms for Cu homeostasis in this pathogenic fungus and identifies potential new pathogen-specific targets for therapeutic intervention in fungal infections.

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