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

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 and Jarrod R. Fortwendel ()
Additional contact information
Jinhong Xie: 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
Ashley V. Nywening: 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

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48767-3

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