The yeast iron regulon is induced upon cobalt stress and crucial for cobalt tolerance

To identify yeast genes involved in cobalt detoxification, we performed RNA expression profiling experiments and followed changes in gene activity upon cobalt stress on a genome-wide scale. We found that cobalt stress specifically results in an immediate and dramatic induction of genes involved in iron uptake. This response is dependent on the Aft1 protein, a transcriptional factor known to regulate a set of genes involved in iron uptake and homeostasis (iron regulon). Like iron starvation, cobalt stress induces accumulation of the Aft1 protein in the nucleus to activate transcription of its target genes. Cells lacking the AFT1 gene (aft1) are hypersensitive to cobalt as well as to other transition metals, whereas expression of the dominant AFT1-1(up) allele, which results in up-regulation of AFT1-controlled genes, confers resistance. Cobalt resistance correlates with an increase in intracellular iron in AFTI-1(up) cells, and sensitivity of aft1 cells is associated with a lack of iron accumulation. Furthermore, elevated iron levels in the growth medium suppress the cobalt sensitivity of the aft1 mutant cells, even though they increase cellular cobalt. Results presented indicate that yeast cells acquire cobalt tolerance by activating the Aft1p-dependent iron regulon and thereby increasing intracellular iron levels.