Methylation of glycosylated sphingolipid modulates membrane lipid topography and pathogenicity of Cryptococcus neoformans: Membrane lipid topography and fungal pathogenicity
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In previous studies we showed that the replication of Cryptococcus neoformans in the lung environment is controlled by the glucosylceramide (GlcCer) synthase gene (GCS1), which synthesizes the membrane sphingolipid GlcCer from the C9-methyl ceramide. Here, we studied the effect of the mutation of the sphingolipid C9 methyltransferase gene (SMT1), which adds a methyl group to position 9 of the sphingosine backbone of ceramide. The C. neoformans Δsmt1 mutant does not make C9-methyl ceramide and, thus, any methylated GlcCer. However, it accumulates demethylated ceramide and demethylated GlcCer. The Δsmt1 mutant loses more than 80% of its virulence compared with the wild type and the reconstituted strain. Interestingly, growth of C. neoformans Δsmt1 in the lung was decreased and C. neoformans cells were contained in lung granulomas, which significantly reduced the rate of their dissemination to the brain reducing the onset of meningoencephalitis. Thus, using fluorescent spectroscopy and atomic force microscopy we compared the wild type and Δsmt1 mutant and found that the altered membrane composition and GlcCer structure affects fungal membrane rigidity, suggesting that specific sphingolipid structures are required for proper fungal membrane organization and integrity. Therefore, we propose that the physical structure of the plasma membrane imparted by specific classes of sphingolipids represents a critical factor for the ability of the fungus to establish virulence.
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Sphingolipid biosynthesis is an attractive target given the function of these lipids in mediating signal transduction, cell regulation and virulence in fungal pathogens.
“Finally, biosynthesis of sphingolipids is emerging as an attractive target given the function of these lipids in mediating signal transduction, cell regulation and virulence in fungal pathogens99.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [99]
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- Authors
- Singh, A., Wang, H., Silva, L. C., Na, C., Prieto, M., Futerman, A. H., Luberto, C., & Del Poeta, M.
- Affiliations
- Medical University of South Carolina (US)
- University of Notre Dame (US)
- University of Lisbon (PT)
- Instituto Superior Técnico (PT)
- Weizmann Institute of Science (IL)
- ORCID
- Venue
- Cellular Microbiology
- Publisher
- Wiley
- Published
- 2012-01-09
- Volume
- 14
- Issue
- 4
- Pages
- 500-516
- ISSN
- 1462-5814 (ISSN-L)
- PMC
- PMC3302964
- OpenAlex
- W1557480900
- Cited by
- 81
- References
- 83
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 2 · 2021: 7 · 2020: 7 · 2019: 6 · 2018: 13 · 2017: 3 · 2016: 5 · 2015: 9 · 2014: 5 · 2013: 1
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cellular Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Medical University of South Carolina
- University of Notre Dame
- National Institutes of Health (1c06rr015455-01a1)
- National Institute of Allergy and Infectious Diseases (R21AI078493, AI087541, AI071142, AI056168, R01AI056168, R01AI071142, AI078493, R56AI087541)
- National Center for Research Resources (C06 RR-015455)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- Cryptococcus neoformans, glucosylceramide, fungal virulence, membrane rigidity, pulmonary infection, meningoencephalitis, granuloma, fungal pathogenesis
- MeSH terms
- Animals, Brain, Cell Membrane, Cell Membrane Permeability, Central Nervous System Infections, Cryptococcosis, Cryptococcus neoformans, Genes, Fungal, Glucosylceramides, Granuloma, Hydrogen-Ion Concentration, Lung, Membrane Lipids, Meningoencephalitis, Methylation, Methyltransferases, Mice, Inbred CBA, Mutation, Spectrometry, Fluorescence, Sphingolipids, Sphingosine, Virulence, Gene Expression Regulation, Fungal, Microscopy, Atomic Force, Mice, Host-Pathogen Interactions
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