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

Xie, Jinhong, Ryback, Jeffrey M., Martin-Vicente, Adela, Guruceaga, Xabier, Thorn, Harrison I., Nywening, Ashley V., Ge, Wenbo, Parker, Josie E., Kelly, Steven L., Rogers, David P. and Fortwendel, Jarrod R. 2024. The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species. Nature Communications 15 , 4261. 10.1038/s41467-024-48767-3

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences
Publisher:	Nature Research
Date of First Compliant Deposit:	13 May 2024
Date of Acceptance:	9 May 2024
Last Modified:	21 May 2024 11:37
URI:	https://orca.cardiff.ac.uk/id/eprint/168871

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