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J. Biol. Chem., Vol. 279, Issue 49, 51669-51676, December 3, 2004

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UDP-glucose Dehydrogenase Plays Multiple Roles in the Biology of the Pathogenic Fungus Cryptococcus neoformans^*

Cara L. Griffith, J. Stacey Klutts¶, Lijuan Zhang||, Steven B. Levery**, and Tamara L. Doering

From the Departments of Molecular Microbiology and Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110 and the ^**Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824

Cryptococcus neoformans is a pathogenic fungus surrounded by an elaborate polysaccharide capsule that is strictly required for its virulence in humans and other mammals. Nearly half of the sugar residues in the capsule are derived from UDP-glucuronic acid or its metabolites. To examine the role of these nucleotide sugars in C. neoformans, the gene encoding UDP-glucose dehydrogenase was disrupted. Mass spectrometry analysis of nucleotide sugar pools showed that the resulting mutant lacked both UDP-glucuronic acid and its downstream product, UDP-xylose, thus confirming the effect of the knockout and indicating that an alternate pathway for UDP-glucuronic acid production was not used. The mutant was dramatically affected by the lack of specific sugar donors, demonstrating altered cell integrity, temperature sensitivity, lack of growth in an animal model of cryptococcosis, and morphological defects. Additionally, the polysaccharide capsule could not be detected on the mutant cells, although the possibility remains that abbreviated forms of capsule components are made, possibly without proper surface display. The capsule defect is largely independent of the other observed changes, as cells that are acapsular because of mutations in other genes show lack of virulence but do not exhibit alterations in cell integrity, temperature sensitivity, or cellular morphology. All of the observed alterations were reversed by correction of the gene disruption.

Received for publication, August 4, 2004 , and in revised form, September 9, 2004.

^* This work was supported in part by National Institutes of Health Grant GM R01 066303 and a Burroughs Wellcome Fund Junior Investigator in Molecular Pathogenic Mycology award (to T. L. D). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by National Institutes of Health Grant GM F32 072341.

^|| Supported by National Institutes of Health Grant GM R01 069968.

Supported by National Institutes of Health Grant NCRR P20 RR16459.

To whom correspondence should be addressed: Campus Box 8230, 660 South Euclid Ave., St. Louis, MO 63110-1093. Tel.: 314-747-5597; Fax: 314-362-1232; E-mail: doering{at}wustl.edu.

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