skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: 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 » 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.« less

Authors:
ORCiD logo; ; ; ORCiD logo;
Publication Date:
Research Org.:
Univ. of Georgia Research Foundation, Inc., 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. doi: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. doi: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 = {2018},
month = {1}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1371/journal.ppat.1006765

Citation Metrics:
Cited by: 3 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Minimizing fungal disease deaths will allow the UNAIDS target of reducing annual AIDS deaths below 500 000 by 2020 to be realized
journal, December 2016

  • Denning, David W.
  • Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 371, Issue 1709
  • DOI: 10.1098/rstb.2015.0468

β1,2-Xylosyltransferase Cxt1p Is Solely Responsible for Xylose Incorporation into Cryptococcus neoformans Glycosphingolipids
journal, August 2008

  • Castle, Sherry A.; Owuor, Elizabeth A.; Thompson, Stephanie H.
  • Eukaryotic Cell, Vol. 7, Issue 9
  • DOI: 10.1128/EC.00458-07

SQV-7, a protein involved in Caenorhabditis elegans epithelial invagination and early embryogenesis, transports UDP-glucuronic acid, UDP-N- acetylgalactosamine, and UDP-galactose
journal, March 2001

  • Berninsone, P.; Hwang, H. -Y.; Zemtseva, I.
  • Proceedings of the National Academy of Sciences, Vol. 98, Issue 7
  • DOI: 10.1073/pnas.061593098

Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation
journal, February 2015

  • Maier, Ezekiel J.; Haynes, Brian C.; Gish, Stacey R.
  • Genome Research, Vol. 25, Issue 5
  • DOI: 10.1101/gr.184101.114

A β-1,2-Xylosyltransferase from Cryptococcus neoformans Defines a New Family of Glycosyltransferases
journal, April 2007

  • Klutts, J. Stacey; Levery, Steven B.; Doering, Tamara L.
  • Journal of Biological Chemistry, Vol. 282, Issue 24
  • DOI: 10.1074/jbc.M701941200

The Arabidopsis Golgi-localized GDP-L-fucose transporter is required for plant development
journal, July 2016

  • Rautengarten, Carsten; Ebert, Berit; Liu, Lifeng
  • Nature Communications, Vol. 7, Issue 1
  • DOI: 10.1038/ncomms12119

Elucidating the immunological function of the Cryptococcus neoformans capsule
journal, September 2013

  • Vecchiarelli, Anna; Pericolini, Eva; Gabrielli, Elena
  • Future Microbiology, Vol. 8, Issue 9
  • DOI: 10.2217/fmb.13.84

How Sweet it is! Cell Wall Biogenesis and Polysaccharide Capsule Formation in Cryptococcus neoformans
journal, October 2009


Split marker transformation increases homologous integration frequency in Cryptococcus neoformans
journal, March 2006


Unusual Galactofuranose Modification of a Capsule Polysaccharide in the Pathogenic Yeast Cryptococcus neoformans
journal, February 2013

  • Heiss, Christian; Skowyra, Michael L.; Liu, Hong
  • Journal of Biological Chemistry, Vol. 288, Issue 16
  • DOI: 10.1074/jbc.M112.441998

Cryptococcus neoformans Dual GDP-Mannose Transporters and Their Role in Biology and Virulence
journal, April 2014

  • Wang, Zhuo A.; Griffith, Cara L.; Skowyra, Michael L.
  • Eukaryotic Cell, Vol. 13, Issue 6
  • DOI: 10.1128/EC.00054-14

BLAST-EXPLORER helps you building datasets for phylogenetic analysis
journal, January 2010

  • Dereeper, Alexis; Audic, Stephane; Claverie, Jean-Michel
  • BMC Evolutionary Biology, Vol. 10, Issue 1
  • DOI: 10.1186/1471-2148-10-8

Cryptococcus neoformans and Cryptococcus gattii, the Etiologic Agents of Cryptococcosis
journal, July 2014

  • Kwon-Chung, K. J.; Fraser, J. A.; Doering, T. L.
  • Cold Spring Harbor Perspectives in Medicine, Vol. 4, Issue 7
  • DOI: 10.1101/cshperspect.a019760

Functional cloning and characterization of a UDP- glucuronic acid decarboxylase: The pathogenic fungus Cryptococcus neoformans elucidates UDP-xylose synthesis
journal, October 2001

  • Bar-Peled, M.; Griffith, C. L.; Doering, T. L.
  • Proceedings of the National Academy of Sciences, Vol. 98, Issue 21
  • DOI: 10.1073/pnas.211229198

Reconstitution of GDP-mannose Transport Activity with Purified Leishmania LPG2 Protein in Liposomes
journal, November 2004

  • Segawa, Hiroaki; Soares, Rodrigo P.; Kawakita, Masao
  • Journal of Biological Chemistry, Vol. 280, Issue 3
  • DOI: 10.1074/jbc.M404915200

Unraveling the Novel Structure and Biosynthetic Pathway of O -Linked Glycans in the Golgi Apparatus of the Human Pathogenic Yeast Cryptococcus neoformans
journal, December 2014

  • Lee, Dong-Jik; Bahn, Yong-Sun; Kim, Hong-Jin
  • Journal of Biological Chemistry, Vol. 290, Issue 3
  • DOI: 10.1074/jbc.M114.607705

Phylogeny.fr: robust phylogenetic analysis for the non-specialist
journal, May 2008

  • Dereeper, A.; Guignon, V.; Blanc, G.
  • Nucleic Acids Research, Vol. 36, Issue Web Server
  • DOI: 10.1093/nar/gkn180

Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans
journal, June 2006

  • Rittershaus, P. C.
  • Journal of Clinical Investigation, Vol. 116, Issue 6
  • DOI: 10.1172/JCI27890

Enzymatic Synthesis of UDP-Galactofuranose and an Assay for UDP-Galactopyranose Mutase Based on High-Performance Liquid Chromatography
journal, November 1996

  • Lee, Robin; Monsey, David; Weston, Anthony
  • Analytical Biochemistry, Vol. 242, Issue 1
  • DOI: 10.1006/abio.1996.0419

β(1,2)-Xylose and α(1,3)-Fucose Residues Have a Strong Contribution in IgE Binding to Plant Glycoallergens
journal, April 2000

  • van Ree, Ronald; Cabanes-Macheteau, Marion; Akkerdaas, Jaap
  • Journal of Biological Chemistry, Vol. 275, Issue 15
  • DOI: 10.1074/jbc.275.15.11451

The structure of Cryptococcus neoformans galactoxylomannan contains β-d-glucuronic acid
journal, May 2009


Cryptococcal Xylosyltransferase 1 (Cxt1p) from Cryptococcus neoformans Plays a Direct Role in the Synthesis of Capsule Polysaccharides
journal, March 2008

  • Klutts, J. Stacey; Doering, Tamara L.
  • Journal of Biological Chemistry, Vol. 283, Issue 21
  • DOI: 10.1074/jbc.M708927200

The Human Solute Carrier Gene SLC35B4 Encodes a Bifunctional Nucleotide Sugar Transporter with Specificity for UDP-Xylose and UDP- N -Acetylglucosamine
journal, May 2005

  • Ashikov, Angel; Routier, Françoise; Fuhlrott, Jutta
  • Journal of Biological Chemistry, Vol. 280, Issue 29
  • DOI: 10.1074/jbc.M504783200

Transporters of nucleotide sugars, nucleotide sulfate and ATP in the Golgi apparatus
journal, June 1997


Identification and Characterization of a Golgi-Localized UDP-Xylose Transporter Family from Arabidopsis
journal, March 2015

  • Ebert, Berit; Rautengarten, Carsten; Guo, Xiaoyuan
  • The Plant Cell, Vol. 27, Issue 4
  • DOI: 10.1105/tpc.114.133827

ngLOC: an n-gram-based Bayesian method for estimating the subcellular proteomes of eukaryotes
journal, January 2007


Systematic capsule gene disruption reveals the central role of galactose metabolism on Cryptococcus neoformans virulence
journal, May 2007


Cryptococcus neoformans UGT1 encodes a UDP-Galactose/UDP-GalNAc transporter
journal, August 2016


The elaborate route for UDP-arabinose delivery into the Golgi of plants
journal, April 2017

  • Rautengarten, Carsten; Birdseye, Devon; Pattathil, Sivakumar
  • Proceedings of the National Academy of Sciences, Vol. 114, Issue 16
  • DOI: 10.1073/pnas.1701894114

Analysis of plant nucleotide sugars by hydrophilic interaction liquid chromatography and tandem mass spectrometry
journal, March 2014


Human and Drosophila UDP-galactose transporters transport UDP-N-acetylgalactosamine in addition to UDP-galactose: UDP-Gal transporter transports UDP-GlcNAc
journal, January 2002


Unraveling Unique Structure and Biosynthesis Pathway of N -Linked Glycans in Human Fungal Pathogen Cryptococcus neoformans by Glycomics Analysis
journal, April 2012

  • Park, Jeong-Nam; Lee, Dong-Jik; Kwon, Ohsuk
  • Journal of Biological Chemistry, Vol. 287, Issue 23
  • DOI: 10.1074/jbc.M112.354209

The Cryptococcus neoformans Rim101 Transcription Factor Directly Regulates Genes Required for Adaptation to the Host
journal, December 2013

  • O'Meara, T. R.; Xu, W.; Selvig, K. M.
  • Molecular and Cellular Biology, Vol. 34, Issue 4
  • DOI: 10.1128/MCB.01359-13

UDP- N -acetylglucosamine transporter and UDP-galactose transporter form heterologous complexes in the Golgi membrane
journal, October 2012


Deciphering the glycogenome of schistosomes
journal, August 2014

  • Mickum, Megan L.; Prasanphanich, Nina S.; Heimburg-Molinaro, Jamie
  • Frontiers in Genetics, Vol. 5
  • DOI: 10.3389/fgene.2014.00262

MUSCLE: multiple sequence alignment with high accuracy and high throughput
journal, March 2004

  • Edgar, R. C.
  • Nucleic Acids Research, Vol. 32, Issue 5, p. 1792-1797
  • DOI: 10.1093/nar/gkh340

Functional Expression of the Murine Golgi CMP-Sialic Acid Transporter in Saccharomyces cerevisiae
journal, May 1997

  • Berninsone, Patricia; Eckhardt, Matthias; Gerardy-Schahn, Rita
  • Journal of Biological Chemistry, Vol. 272, Issue 19
  • DOI: 10.1074/jbc.272.19.12616

The Golgi localized bifunctional UDP-rhamnose/UDP-galactose transporter family of Arabidopsis
journal, July 2014

  • Rautengarten, C.; Ebert, B.; Moreno, I.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 31
  • DOI: 10.1073/pnas.1406073111

TreeDyn: towards dynamic graphics and annotations for analyses of trees
journal, October 2006

  • Chevenet, François; Brun, Christine; Bañuls, Anne-Laure
  • BMC Bioinformatics, Vol. 7, Issue 1
  • DOI: 10.1186/1471-2105-7-439

Cryptococcus and Phagocytes: Complex Interactions that Influence Disease Outcome
journal, February 2016

  • Leopold Wager, Chrissy M.; Hole, Camaron R.; Wozniak, Karen L.
  • Frontiers in Microbiology, Vol. 7
  • DOI: 10.3389/fmicb.2016.00105

A Simple, Fast, and Accurate Algorithm to Estimate Large Phylogenies by Maximum Likelihood
journal, October 2003


    Works referencing / citing this record:

    Amino Acid Metabolism and Transport Mechanisms as Potential Antifungal Targets
    journal, March 2018

    • McCarthy, Matthew; Walsh, Thomas
    • International Journal of Molecular Sciences, Vol. 19, Issue 3
    • DOI: 10.3390/ijms19030909