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Changes in glucosylceramide structure affect virulence and membrane biophysical properties of Cryptococcus neoformans

Raj, S; Nazemidashtarjandi, S; Kim, J; Joffe, L; Zhang, X; Singh, A; Mor, V; ... Farnoud, AM; + view all (2017) Changes in glucosylceramide structure affect virulence and membrane biophysical properties of Cryptococcus neoformans. Biochimica et Biophysica Acta (BBA) - Biomembranes , 1859 (11) pp. 2224-2233. 10.1016/j.bbamem.2017.08.017. Green open access

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Abstract

Fungal glucosylceramide (GlcCer) is a plasma membrane sphingolipid in which the sphingosine backbone is unsaturated in carbon position 8 (C8) and methylated in carbon position 9 (C9). Studies in the fungal pathogen, Cryptococcus neoformans, have shown that loss of GlcCer synthase activity results in complete loss of virulence in the mouse model. However, whether the loss of virulence is due to the lack of the enzyme or to the loss of the sphingolipid is not known. In this study, we used genetic engineering to alter the chemical structure of fungal GlcCer and studied its effect on fungal growth and pathogenicity. Here we show that unsaturation in C8 and methylation in C9 is required for virulence in the mouse model without affecting fungal growth in vitro or common virulence factors. However, changes in GlcCer structure led to a dramatic susceptibility to membrane stressors resulting in increased cell membrane permeability and rendering the fungal mutant unable to grow within host macrophages. Biophysical studies using synthetic vesicles containing GlcCer revealed that the saturated and unmethylated sphingolipid formed vesicles with higher lipid order that were more likely to phase separate into ordered domains. Taken together, these studies show for the first time that a specific structure of GlcCer is a major regulator of membrane permeability required for fungal pathogenicity.

Type: Article
Title: Changes in glucosylceramide structure affect virulence and membrane biophysical properties of Cryptococcus neoformans
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bbamem.2017.08.017
Publisher version: http://doi.org/10.1016/j.bbamem.2017.08.017
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Sphingolipid; fungi; infectious disease; plasma membrane; Cryptococcus; glucosylceramide
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10062894
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