FIG 8 .

Model for the role of Atm1 during Cu stress in C. neoformans. In C. neoformans, Cuf1 is the primary transcription factor that regulates the expression of genes required for maintaining Cu homeostasis, either when Cu is scarce or when the concentrations approach toxic levels. When Cu concentrations approach toxic levels, Cuf1 occupancy is no longer enriched at promoters of genes with roles in Cu acquisition, as exemplified by the Cu importers Ctr1 and Ctr4, preventing the acquisition of more Cu⁺ from the environment. At the same time, Cuf1 occupancy is enriched at the MT1 and MT2 promoters, inducing the expression of the Mt1 and Mt2 proteins which sequester Cu, as they have high affinity and high binding capacity for this metal. The Cuf1-dependent and Cu-dependent induction of the expression of the mitochondrial ABC transporter Atm1 with a role in cytosolic and nuclear Fe-S protein biogenesis provides a novel way for coping with Cu toxicity. Fe-S proteins, which have many important and essential cellular functions, are major targets for Cu toxicity. Cu activation of Atm1 expression contributes to preservation of the homeostasis of cytosolic-nuclear Fe-S proteins, in particular, those with essential cellular functions, in the presence of toxic amounts of this metal.