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The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
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The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
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Journal Article
The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
2024
Overview
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.
Antifungal triazoles inhibit biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Here, Xie et al. show that Erg6, the enzyme that catalyzes a previous step in ergosterol biosynthesis, is essential for the viability of
Aspergillus fumigatus
, and its repression reduces the virulence of this fungal pathogen in an animal model of infection.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/22
/ 38/35
/ 38/39
/ 38/70
/ 38/77
/ 42/70
/ Animals
/ Antifungal Agents - pharmacology
/ Aspergillosis - drug therapy
/ Aspergillosis - microbiology
/ Aspergillus fumigatus - drug effects
/ Aspergillus fumigatus - enzymology
/ Aspergillus fumigatus - genetics
/ Aspergillus fumigatus - metabolism
/ Enzymes
/ Female
/ Fungal Proteins - metabolism
/ Fungi
/ Gene Expression Regulation, Fungal
/ Humanities and Social Sciences
/ Hyphae
/ Hyphae - growth & development
/ Lipids
/ Methyltransferases - genetics
/ Methyltransferases - metabolism
/ Mice
/ Science
/ Sterols
/ Yeast
