Genome‐wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans

What is it about?

The essential yet toxic nature of Cu ions in living cells requires exquisite control of Cu homeostasis. The fungal pathogen C. neoformans regulates Cu homeostasis for survival during its complex host colonization process. During pulmonary infection host innate immune cells use Cu to kill C. neoformans, which responds by activating expression of Cu detoxifying proteins. However, during brain colonization, expression of the fungal Cu import machinery is activated and required for virulence. To achieve the genetic plasticity required for adaptation to a continuum of distinct Cu environments within the host, C. neoformans utilizes the Cu-responsive transcription factor, Cuf1. Cuf1 is unique as it senses and responds to both high and low Cu environments, activating different sets of genes dependent on environmental Cu status. Cells lacking Cuf1 are compromised for colonization of the lungs and brain, highlighting Cuf1 as an important virulence factor. A genome-wide assessment of Cuf1 binding sites and Cuf1-dependent transcription changes driven by Cu status identified novel genes required for adaptation to differential Cu environments. These genes and their regulation provide new insights into the adaptive responses to changes in host Cu availability and may reveal new targets for therapeutic intervention in cryptococcosis.

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