Abstract
Most fungi express two transcription factors that regulate the expression of genes associated with copper uptake for nutritional needs, and with copper resistance when copper approaches a cytotoxic level. These factors are characterized by cysteine-rich motifs which are associated with copper-sensing, DNA-binding and release, and/or cytoplasmic retention. Cryptococcus neoformans differs from most in that it expresses a single such copper-sensing trans-factor, Cuf1, a protein that up-regulates copper uptake when copper is scarce, and up-regulates copper sequestration when cells become super-replete. For C. neoformans this is an essential task in as much as copper is relatively bioavailable in lung airways while the brain interstitium can be copper-limiting for growth. While fungal dependence on and sensitivity to copper have long been considered targets for anti-fungal chemistry, fungi have proven adept at finding 'work arounds' by using a chelated form of copper as nutrient or adapting to a copper-surfaced hospital bed by increased resistance. However, the cohort of Cuf1 targets identified in this report represent far more than just the uptake and sequestration machinery, but include additional loci that, perhaps, are less easily 'defended' by the fungus. Garcia-Santamarina et al. provide that list and thus lay the ground-work for developing novel anti-fungal reagents.