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

• Published in: Nature communications Vol. 15; no. 1; p. 4261
• Main Authors: Xie, Jinhong, Rybak, Jeffrey M, Martin-Vicente, Adela, Guruceaga, Xabier, Thorn, Harrison I, Nywening, Ashley V, Ge, Wenbo, Parker, Josie E, Kelly, Steven L, Rogers, P David, Fortwendel, Jarrod R
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 20.05.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animal models; Animals; Antifungal Agents - pharmacology; Aspergillosis; Aspergillosis - drug therapy; Aspergillosis - microbiology; Aspergillus; Aspergillus - genetics; Aspergillus fumigatus; Aspergillus fumigatus - drug effects; Aspergillus fumigatus - enzymology; Aspergillus fumigatus - genetics; Aspergillus fumigatus - metabolism; Biosynthesis; Enzymes; Ergosterol; Ergosterol - biosynthesis; Ergosterol - metabolism; Female; Fungal Proteins - genetics; Fungal Proteins - metabolism; Fungi; Fungicides; Gene Expression Regulation, Fungal; Hyphae; Hyphae - drug effects; Hyphae - genetics; Hyphae - growth & development; Hyphae - metabolism; Lipids; Membranes; Methyltransferase; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Microbial Sensitivity Tests; Pathogens; Sterols; Therapeutic targets; Triazoles; Triazoles - pharmacology; Viability; Virulence; Virulence - genetics; Yeasts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48767-3

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.