Cobalt chloride, a hypoxia-mimicking agent, targets sterol synthesis in the pathogenic fungus Cryptococcus neoformans

We investigated the effects of the hypoxia-mimetic CoCl₂ in the pathogenic fungus Cryptococcus neoformans and demonstrated that CoCl₂ leads to defects in several enzymatic steps in ergosterol biosynthesis. Sterol defects were amplified in cells lacking components of the Sre1p-mediated oxygen-sensing pathway. Consequently, Sre1p and its binding partner Scp1p were essential for growth in the presence of CoCl₂. Interestingly, high copies of a single gene involved in ergosterol biosynthesis, ERG25, rescued this growth defect. We show that the inhibitory effect of CoCl₂ on scp1Δ and sre1Δ cells likely resulted from either an accumulation of non-viable methylated sterols or a decrease in the amount of ergosterol. Similar findings were also observed in the ascomycetous yeast, Schizosaccharomyces pombe, suggesting that the effects of CoCl₂ on the Sre1p-mediated response are conserved in fungi. In addition, gene expression analysis revealed limited overlap between Sre1p-dependant gene activation in the presence of CoCl₂ and low oxygen. The majority of genes similarly affected by both CoCl₂ and low oxygen were involved in ergosterol synthesis and in iron/copper transport. This article identifies the Sre1p pathway as a common mechanism by which yeast cells sense and adapt to changes in both CoCl₂ concentrations and oxygen levels.