Systematic Analysis Of C.Neoformans Cu Regulons Reveals The Critical Function Of Cu Homeostasis In Fungal Virulence

C.neoformans is pathogenic fungus that can cause lethal meningoencephalitisin mammals,leading over?600,000 deaths annually.Numerous studies have demonstrated that C.neoformans copper homeostasis is important for fungal virulence.Fungal cells encounter dramatic copper levels in various host tissues during infections,and manipulate the expression of Cu-responsive genesin response to environmental copper levels in the lung and brain.The genome of C.neoformans encodes many Cu regulons,but their roles in fungal virulence are poorly characterized.In current study,we analyze Cu transporters Ctr2 and Ccc2,Cu chaperone Atxl and Ccs,and a laccase potein Lacl,to study the correlation between the Cu-responsive gene functions and fungal virulence,and potential Cu-responsive protein-protein interactions.Our results showed that 1)The loss of Ctr2 causes an increased cell proliferation in the lung,in comparsion to the wild-type strain.2)Proteins,Atxl,Ccc2 and Lac 1 forms a hetero-trimer complex for Cu loading onto Lac 1 to produce melanin.3)Ccc2 is a Cu transporter on golgi compartment and plays an essential role in cell growth.In addition,our data implies the existence of an unknowncopper chaperone,which delivers Cu to Ccc2.4)Ccs is utilized by fungal cells as a Cu overload defense mechanism.