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Erg6 affects membrane composition and virulence of the human fungal pathogen Cryptococcus neoformans.

Publication ,  Journal Article
Oliveira, FFM; Paes, HC; Peconick, LDF; Fonseca, FL; Marina, CLF; Bocca, AL; Homem-de-Mello, M; Rodrigues, ML; Albuquerque, P; Nicola, AM ...
Published in: Fungal Genet Biol
July 2020

Ergosterol is the most important membrane sterol in fungal cells and a component not found in the membranes of human cells. We identified the ERG6 gene in the AIDS-associated fungal pathogen, Cryptococcus neoformans, encoding the sterol C-24 methyltransferase of fungal ergosterol biosynthesis. In this work, we have explored its relationship with high-temperature growth and virulence of C. neoformans by the construction of a loss-of-function mutant. In contrast to other genes involved in ergosterol biosynthesis, C. neoformans ERG6 is not essential for growth under permissive conditions in vitro. However, the erg6 mutant displayed impaired thermotolerance and increased susceptibility to osmotic and oxidative stress, as well as to different antifungal drugs. Total lipid analysis demonstrated a decrease in the erg6Δ strain membrane ergosterol content. In addition, this mutant strain was avirulent in an invertebrate model of C. neoformans infection. C. neoformans Erg6 was cyto-localized in the endoplasmic reticulum and Golgi complex. Our results demonstrate that Erg6 is crucial for growth at high temperature and virulence, likely due to its effects on C. neoformans membrane integrity and dynamics. These pathogen-focused investigations into ergosterol biosynthetic pathway components reinforce the multiple roles of ergosterol in the response of diverse fungal species to alterations in the environment, especially that of the infected host. These studies open perspectives to understand the participation of ergosterol in mechanism of resistance to azole and polyene drugs. Observed synergistic growth defects with co-inhibition of Erg6 and other components of the ergosterol biosynthesis pathway suggests novel approaches to treatment in human fungal infections.

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Published In

Fungal Genet Biol

DOI

EISSN

1096-0937

Publication Date

July 2020

Volume

140

Start / End Page

103368

Location

United States

Related Subject Headings

  • Virulence
  • Mutation
  • Microbiology
  • Methyltransferases
  • Humans
  • Gene Expression Regulation, Fungal
  • Ergosterol
  • Endoplasmic Reticulum
  • Cryptococcus neoformans
  • Cryptococcosis
 

Citation

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Oliveira, F. F. M., Paes, H. C., Peconick, L. D. F., Fonseca, F. L., Marina, C. L. F., Bocca, A. L., … Fernandes, L. (2020). Erg6 affects membrane composition and virulence of the human fungal pathogen Cryptococcus neoformans. Fungal Genet Biol, 140, 103368. https://doi.org/10.1016/j.fgb.2020.103368
Oliveira, Fabiana Freire M., Hugo Costa Paes, Luísa Defranco F. Peconick, Fernanda L. Fonseca, Clara Luna Freitas Marina, Anamélia Lorenzetti Bocca, Mauricio Homem-de-Mello, et al. “Erg6 affects membrane composition and virulence of the human fungal pathogen Cryptococcus neoformans.Fungal Genet Biol 140 (July 2020): 103368. https://doi.org/10.1016/j.fgb.2020.103368.
Oliveira FFM, Paes HC, Peconick LDF, Fonseca FL, Marina CLF, Bocca AL, et al. Erg6 affects membrane composition and virulence of the human fungal pathogen Cryptococcus neoformans. Fungal Genet Biol. 2020 Jul;140:103368.
Oliveira, Fabiana Freire M., et al. “Erg6 affects membrane composition and virulence of the human fungal pathogen Cryptococcus neoformans.Fungal Genet Biol, vol. 140, July 2020, p. 103368. Pubmed, doi:10.1016/j.fgb.2020.103368.
Oliveira FFM, Paes HC, Peconick LDF, Fonseca FL, Marina CLF, Bocca AL, Homem-de-Mello M, Rodrigues ML, Albuquerque P, Nicola AM, Alspaugh JA, Felipe MSS, Fernandes L. Erg6 affects membrane composition and virulence of the human fungal pathogen Cryptococcus neoformans. Fungal Genet Biol. 2020 Jul;140:103368.
Journal cover image

Published In

Fungal Genet Biol

DOI

EISSN

1096-0937

Publication Date

July 2020

Volume

140

Start / End Page

103368

Location

United States

Related Subject Headings

  • Virulence
  • Mutation
  • Microbiology
  • Methyltransferases
  • Humans
  • Gene Expression Regulation, Fungal
  • Ergosterol
  • Endoplasmic Reticulum
  • Cryptococcus neoformans
  • Cryptococcosis