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PreprintCited by 11Fungal and yeast genetics researchAntifungal resistance and susceptibilityFungal Infections and Studies

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Lipid transport by Candida albicans Dnf2 is required for hyphal growth and virulence

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Jain, Bhawik K., Wagner, Andrew S., Reynolds, Todd B., Graham, Todd R.·2022·Infection and Immunity
DOI 10.1101/2022.06.10.495726PMC PMC9670988

Preprint — published as 10.1128/iai.00416-22 · Paper page

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Abstract

Candida albicans is a common cause of human mucosal yeast infections, and invasive candidiasis can be fatal. Antifungal medications are limited, but those targeting the pathogen cell wall or plasma membrane have been effective. Therefore, virulence factors controlling membrane biogenesis are potential targets for drug development. P4-ATPases contribute to membrane biogenesis by selecting and transporting specific lipids from the extracellular leaflet to the cytoplasmic leaflet of the bilayer to generate lipid asymmetry. A subset of heterodimeric P4-ATPases, including Dnf1-Lem3 and Dnf2-Lem3 from Saccharomyces cerevisiae , transport phosphatidylcholine (PC), phosphatidylethanolamine (PE), and the sphingolipid glucosylceramide (GlcCer). GlcCer is a critical lipid for Candida albicans polarized growth and virulence, but the role of GlcCer transporters in virulence has not been explored. Here we show that the Candida albicans Dnf2 ( Ca Dnf2) requires association with Ca Lem3 to form a functional transporter and flip fluorescent derivatives of GlcCer, PC and PE across the plasma membrane. Mutation of conserved substrate-selective residues in the membrane domain strongly abrogates GlcCer transport and partially disrupts PC transport by CaDnf2. Candida strains harboring dnf2 null alleles ( dnf2 ΔΔ) or point mutations that disrupt substrate recognition exhibit defects in the yeast to hyphal growth transition, filamentous growth and virulence in systemically infected mice. The influence of CaDNF1 deletion on the morphological phenotypes is negligible although the dnf1 ΔΔ dnf2 ΔΔ strain was less virulent than the dnf2 ΔΔ strain. These results indicate that the transport of GlcCer and/or PC by plasma membrane P4-ATPases is important for pathogenicity of Candida albicans .

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Metadata

Authors
Jain, B. K., Wagner, A. S., Reynolds, T. B., & Graham, T. R.
Affiliations
  • Vanderbilt University (US)
  • University of Tennessee at Knoxville (US)
Corresponding author
Graham, Todd R.
ORCID
Venue
Infection and Immunity
Publisher
openRxiv
Published
2022-06-11
Volume
90
Issue
11
Pages
e0041622-e0041622
ISSN
0019-9567 (ISSN-L)
DOI
10.1101/2022.06.10.495726
PMC
PMC9670988
OpenAlex
W4303986632
Cited by
11
References
1
Citations by year
2026: 2 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 1
FWCI
0.73
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Infection and Immunity (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Vanderbilt University
  • Vanderbilt University Medical Center
  • Stony Brook University
  • National Institutes of Health (1R01AI53599-01)
  • National Cancer Institute (P30CA068485)
  • National Institute of General Medical Sciences (R35GM144123)
  • National Institute of Allergy and Infectious Diseases (R01AI153599, R01AI035997)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK058404)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
Keywords
Candida albicans, lipid transport, hyphal growth, virulence, invasive candidiasis, fungal pathogenesis, antifungal resistance
MeSH terms
Adenosine Triphosphatases, Animals, Candida albicans, Humans, Saccharomyces cerevisiae, Virulence, ATP-Binding Cassette Transporters, Hyphae, Membrane Transport Proteins, Saccharomyces cerevisiae Proteins, Mice

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