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The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

Author

Listed:
  • Jinhong Xie

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Jeffrey M. Rybak

    (St. Jude Children’s Research Hospital)

  • Adela Martin-Vicente

    (University of Tennessee Health Science Center)

  • Xabier Guruceaga

    (University of Tennessee Health Science Center)

  • Harrison I. Thorn

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Ashley V. Nywening

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Wenbo Ge

    (St. Jude Children’s Research Hospital)

  • Josie E. Parker

    (Cardiff University)

  • Steven L. Kelly

    (Swansea University Medical School)

  • P. David Rogers

    (St. Jude Children’s Research Hospital)

  • Jarrod R. Fortwendel

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

Abstract

Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target.

Suggested Citation

  • Jinhong Xie & Jeffrey M. Rybak & Adela Martin-Vicente & Xabier Guruceaga & Harrison I. Thorn & Ashley V. Nywening & Wenbo Ge & Josie E. Parker & Steven L. Kelly & P. David Rogers & Jarrod R. Fortwende, 2024. "The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48767-3
    DOI: 10.1038/s41467-024-48767-3
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    References listed on IDEAS

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    1. Takanori Furukawa & Norman van Rhijn & Marcin Fraczek & Fabio Gsaller & Emma Davies & Paul Carr & Sara Gago & Rachael Fortune-Grant & Sayema Rahman & Jane Mabey Gilsenan & Emma Houlder & Caitlin H. Ko, 2020. "The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
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    Cited by:

    1. Adela Martin-Vicente & Ana Camila Oliveira Souza & Xabier Guruceaga & Harrison I. Thorn & Jinhong Xie & Ashley V. Nywening & Wenbo Ge & Jarrod R. Fortwendel, 2024. "A conserved fungal morphogenetic kinase regulates pathogenic growth in response to carbon source diversity," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Hesham Elsaman & Evgeny Golubtsov & Sean Brazil & Natanya Ng & Isabel Klugherz & Ronny Martin & Karl Dichtl & Christoph Müller & Johannes Wagener, 2024. "Toxic eburicol accumulation drives the antifungal activity of azoles against Aspergillus fumigatus," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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