Xie, JinhongRybak, Jeffrey M.Martín-Vicente, AdelaGuruceaga Sierra, XabierThorn, Harrison I.Nywening, Ashley V.Ge, WenboParker, Josie E.Kelly, Steven L.Rogers, P. DavidFortwendel, Jarrod R.2024-12-042024-12-042024-05-20Xie, J., Rybak, J. M., Martin-Vicente, A., Guruceaga, X., Thorn, H. I., Nywening, A. V., Wenbo, G., Parker, J. E., Kelly, S. L., Rogers, P. D., Fortwendel, J. R. (2024). The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species. Nature Communications, 15, 1-13. https://doi.org/10.1038/s41467-024-48767-3.2041-172310.1038/s41467-024-48767-3https://academica-e.unavarra.es/handle/2454/52639Triazoles, 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.application/pdfspa© The author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International LicenseErgosterol biosynthesisErg6 enzymeAspergillus fumigatus viabilityAntifungal resistanceinfo:eu-repo/semantics/article2024-12-04info:eu-repo/semantics/openAccess