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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 <jats:italic>Aspergillus fumigatus<\/jats:italic> remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of <jats:italic>A. fumigatus<\/jats:italic> and other <jats:italic>Aspergillus<\/jats:italic> species, including <jats:italic>A. lentulus<\/jats:italic>, <jats:italic>A. terreus<\/jats:italic>, and A. nidulans. Downregulation of <jats:italic>erg6<\/jats:italic> 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, <jats:italic>erg6<\/jats:italic>-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that <jats:italic>erg6<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41467-024-48767-3","type":"journal-article","created":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T08:01:26Z","timestamp":1716192086000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8994-6606","authenticated-orcid":false,"given":"Jinhong","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9317-0935","authenticated-orcid":false,"given":"Jeffrey M.","family":"Rybak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adela","family":"Martin-Vicente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3258-2482","authenticated-orcid":false,"given":"Xabier","family":"Guruceaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2546-8400","authenticated-orcid":false,"given":"Harrison I.","family":"Thorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley V.","family":"Nywening","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3855-4194","authenticated-orcid":false,"given":"Josie E.","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7991-5040","authenticated-orcid":false,"given":"Steven L.","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. 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