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J. Biol. Chem., Vol. 278, Issue 48, 47724-47730, November 28, 2003

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An -1,3-Mannosyltransferase of Cryptococcus neoformans^*

Ulf Sommer, Hong Liu, and Tamara L. Doering

From the Department of Molecular Microbiology, Washington University Medical School, St. Louis, Missouri 63110

Cryptococcus neoformans is a pathogenic fungus, distinguished by an elaborate polysaccharide capsule that is essential for its virulence. As part of an effort to understand the biosynthesis of this important structure, we initiated purification of an -1,3-mannosyltransferase with appropriate specificity for a role in building the main capsule polysaccharide, glucuronoxylomannan. A pool of proteins that was 5,000-fold enriched in this activity included several polypeptides, which acted potentially as the catalytic protein. These were analyzed using sequence information and double-stranded RNA interference. Interference that targeted a sequence corresponding to part of a 46 kDa protein in the enriched fraction abolished the activity of interest and reduced the capsule on the affected cells. This gene was cloned and expressed in active form in Saccharomyces cerevisiae to confirm function, and was termed CMT1, for cryptococcal mannosyltransferase 1. CMT1 has no confirmed homologs in GenBank^TM other than CAP59, a cryptococcal gene encoding a protein of unknown function that is required for capsule synthesis and virulence. The Cmt1p protein also co-purifies with a homolog of CAP64, a gene whose product has similarly been implicated in capsule synthesis and virulence. A strain disrupted in CMT1 was generated in C. neoformans; this had no effect on virulence in an animal model of cryptococcosis.

Received for publication, July 7, 2003 , and in revised form, September 11, 2003.

^* This work was supported by National Institutes of Health Grant R01 AI49173 and a GRANT Award from Neose Technologies, and the Andrew and Virginia Craig Faculty Research Fund. 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.

Current address: Mass Spectrometry Resource, Boston University School of Medicine, Boston, MA.

A Burroughs Wellcome Fund Junior Investigator in Molecular Pathogenic Mycology. 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}borcim.wustl.edu.

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