Xylose donor transport is critical for fungal virulence
Abstract
Cryptococcus neoformans, an AIDS-defining opportunistic pathogen, is the leading cause of fungal meningitis worldwide and is responsible for hundreds of thousands of deaths annually. Cryptococcal glycans are required for fungal survival in the host and for pathogenesis. Most glycans are made in the secretory pathway, although the activated precursors for their synthesis, nucleotide sugars, are made primarily in the cytosol. Nucleotide sugar transporters are membrane proteins that solve this topological problem, by exchanging nucleotide sugars for the corresponding nucleoside phosphates. The major virulence factor of C. neoformans is an anti-phagocytic polysaccharide capsule that is displayed on the cell surface; capsule polysaccharides are also shed from the cell and impede the host immune response. Xylose, a neutral monosaccharide that is absent from model yeast, is a significant capsule component. Here we show that Uxt1 and Uxt2 are both transporters specific for the xylose donor, UDP-xylose, although they exhibit distinct subcellular localization, expression patterns, and kinetic parameters. Both proteins also transport the galactofuranose donor, UDP-galactofuranose. We further show that Uxt1 and Uxt2 are required for xylose incorporation into capsule and protein; they are also necessary for C. neoformans to cause disease in mice, although surprisingly not for fungal viability in the contextmore »
- Publication Date:
- Research Org.:
- Univ. of Georgia, Athens, GA (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH); National Science Foundation (NSF)
- OSTI Identifier:
- 1417423
- Alternate Identifier(s):
- OSTI ID: 1499894
- Grant/Contract Number:
- FG02-93ER20097; FG02-96ER20220; 0090281; R21 AI109623; R01 GM066303; R01 AI087794
- Resource Type:
- Published Article
- Journal Name:
- PLoS Pathogens
- Additional Journal Information:
- Journal Name: PLoS Pathogens Journal Volume: 14 Journal Issue: 1; Journal ID: ISSN 1553-7374
- Publisher:
- Public Library of Science (PLoS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Li, Lucy X., Rautengarten, Carsten, Heazlewood, Joshua L., Doering, Tamara L., and May, ed., Robin Charles. Xylose donor transport is critical for fungal virulence. United States: N. p., 2018.
Web. doi:10.1371/journal.ppat.1006765.
Li, Lucy X., Rautengarten, Carsten, Heazlewood, Joshua L., Doering, Tamara L., & May, ed., Robin Charles. Xylose donor transport is critical for fungal virulence. United States. https://doi.org/10.1371/journal.ppat.1006765
Li, Lucy X., Rautengarten, Carsten, Heazlewood, Joshua L., Doering, Tamara L., and May, ed., Robin Charles. Thu .
"Xylose donor transport is critical for fungal virulence". United States. https://doi.org/10.1371/journal.ppat.1006765.
@article{osti_1417423,
title = {Xylose donor transport is critical for fungal virulence},
author = {Li, Lucy X. and Rautengarten, Carsten and Heazlewood, Joshua L. and Doering, Tamara L. and May, ed., Robin Charles},
abstractNote = {Cryptococcus neoformans, an AIDS-defining opportunistic pathogen, is the leading cause of fungal meningitis worldwide and is responsible for hundreds of thousands of deaths annually. Cryptococcal glycans are required for fungal survival in the host and for pathogenesis. Most glycans are made in the secretory pathway, although the activated precursors for their synthesis, nucleotide sugars, are made primarily in the cytosol. Nucleotide sugar transporters are membrane proteins that solve this topological problem, by exchanging nucleotide sugars for the corresponding nucleoside phosphates. The major virulence factor of C. neoformans is an anti-phagocytic polysaccharide capsule that is displayed on the cell surface; capsule polysaccharides are also shed from the cell and impede the host immune response. Xylose, a neutral monosaccharide that is absent from model yeast, is a significant capsule component. Here we show that Uxt1 and Uxt2 are both transporters specific for the xylose donor, UDP-xylose, although they exhibit distinct subcellular localization, expression patterns, and kinetic parameters. Both proteins also transport the galactofuranose donor, UDP-galactofuranose. We further show that Uxt1 and Uxt2 are required for xylose incorporation into capsule and protein; they are also necessary for C. neoformans to cause disease in mice, although surprisingly not for fungal viability in the context of infection. These findings provide a starting point for deciphering the substrate specificity of an important class of transporters, elucidate a synthetic pathway that may be productively targeted for therapy, and contribute to our understanding of fundamental glycobiology.},
doi = {10.1371/journal.ppat.1006765},
journal = {PLoS Pathogens},
number = 1,
volume = 14,
place = {United States},
year = {Thu Jan 18 00:00:00 EST 2018},
month = {Thu Jan 18 00:00:00 EST 2018}
}
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