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

doi:10.1111/j.1365-2958.2007.05844.x

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Wiley InterScience

Molecular Microbiology

Volume 65 Issue 4, Pages 1018 - 1033

Published Online: 21 Jul 2007

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

Hyeseung Lee, ^1† Clara M. Bien, ^2† Adam L. Hughes, ² Peter J. Espenshade, ² Kyung J. Kwon-Chung ¹ and Yun C. Chang ¹*

¹ Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA.
² Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Correspondence to *E-mail ychang@niaid.nih.gov; Tel. (+1) 301 496 8839; Fax (+1) 301 480 3240.

^† These authors contributed equally to this work.

ABSTRACT

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.