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Eukaryotic Cell, November 2009, p. 1770-1779, Vol. 8, No. 11
1535-9778/09/$08.00+0     doi:10.1128/EC.00207-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Conservation of the Sterol Regulatory Element-Binding Protein Pathway and Its Pathobiological Importance in Cryptococcus neoformans{triangledown}

Yun C. Chang,1 Susham S. Ingavale,1 Clara Bien,2 Peter Espenshade,2 and Kyung J. Kwon-Chung1*

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,1 Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 212052

Received 16 July 2009/ Accepted 8 September 2009

The mammalian sterol regulatory element-binding protein (SREBP) homolog, Sre1, is important for adaptation and growth of Cryptococcus neoformans in the mouse brain, where oxygen concentration and nutritional conditions are suboptimal for fungal growth. The extent of conservation of the SREBP pathway in C. neoformans or in any other fungi, however, has not been investigated. We generated mutants susceptible to low oxygen and identified six genes that play a role in the SREBP pathway. Three of these genes (SFB2, KAP123, and GSK3) are not known to be involved in the SREBP pathway in other fungi. Furthermore, we show that C. neoformans contains an additional gene, DAM1, which functions in the SREBP pathway but is yet to be described. Mutants associated with the steps prior to formation of the nuclear Sre1 form dramatically reduced accumulation of the nuclear form under low-oxygen conditions. Concurrently, two mutant strains, scp1{Delta} and stp1{Delta}, and the previously isolated sre1{Delta} strain showed reduction in ergosterol levels, hypersensitivity to several chemical agents, including azole antifungals, CoCl2, and compounds producing reactive oxygen or nitrogen species, and most importantly, reduced virulence in mice. Mutants affecting genes involved in later steps of the Sre1 pathway, such as those required for import and phosphorylation of proteins in the nucleus, showed less compelling phenotypes. These findings suggest that the SREBP pathway is highly conserved in C. neoformans and it serves as an important link between sterol biosynthesis, oxygen sensing, CoCl2 sensitivity, and virulence in C. neoformans.

* Corresponding author. Mailing address: LCID, NIAID, Building 10, Room 11C304, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-1602. Fax: (301) 480-3240. E-mail: June_Kwon-Chung{at}nih.gov

{triangledown} Published ahead of print on 11 September 2009.

Eukaryotic Cell, November 2009, p. 1770-1779, Vol. 8, No. 11
1535-9778/09/$08.00+0     doi:10.1128/EC.00207-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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