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Cobalt chloride, a hypoxia‐mimicking agent, targets sterol synthesis in the pathogenic fungus Cryptococcus neoformans
Author(s) -
Lee Hyeseung,
Bien Clara M.,
Hughes Adam L.,
Espenshade Peter J.,
KwonChung Kyung J.,
Chang Yun C.
Publication year - 2007
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.2007.05844.x
Subject(s) - ergosterol , biology , cryptococcus neoformans , schizosaccharomyces pombe , sterol , yeast , biochemistry , microbiology and biotechnology , gene , biosynthesis , saccharomyces cerevisiae , cholesterol
Summary We investigated the effects of the hypoxia‐mimetic CoCl 2 in the pathogenic fungus Cryptococcus neoformans and demonstrated that CoCl 2 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 CoCl 2 . Interestingly, high copies of a single gene involved in ergosterol biosynthesis, ERG25 , rescued this growth defect. We show that the inhibitory effect of CoCl 2 on scp1 Δ and sre1 Δ 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 CoCl 2 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 CoCl 2 and low oxygen. The majority of genes similarly affected by both CoCl 2 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 CoCl 2 concentrations and oxygen levels.