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Alliance"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:p>Azoles are first-line therapeutics for human and plant fungal infections, but their broad use has promoted the development of resistances. Recently, a pan-azole\u2013resistant clinical <jats:italic>Aspergillus fumigatus<\/jats:italic> isolate was identified to carry the mutation P88L in subunit HapE of the CCAAT-binding complex (CBC), a conserved eukaryotic transcription factor. Here, we define the mechanistic basis for resistance in this isolate by showing that the HapE<jats:sup>P88L<\/jats:sup> mutation interferes with the CBC\u2019s ability to bend and sense CCAAT motifs. This failure leads to transcriptional derepression of the <jats:italic>cyp51A<\/jats:italic> gene, which encodes the target of azoles, the 14-\u03b1 sterol demethylase Cyp51A, and ultimately causes drug resistance. In addition, we demonstrate that the CBC-associated transcriptional regulator HapX assists <jats:italic>cyp51A<\/jats:italic> repression in low-iron environments and that this iron-dependent effect is lost in the HapE<jats:sup>P88L<\/jats:sup> mutant. Altogether, these results indicate that the mutation HapE<jats:sup>P88L<\/jats:sup> confers increased resistance to azoles compared with wt <jats:italic>A. fumigatus<\/jats:italic>, particularly in low-iron clinical niches such as the lung.<\/jats:p>","DOI":"10.26508\/lsa.202000729","type":"journal-article","created":{"date-parts":[[2020,5,28]],"date-time":"2020-05-28T20:16:43Z","timestamp":1590697003000},"page":"e202000729","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":25,"title":["Structural basis of HapE<sup>P88L<\/sup>-linked antifungal triazole resistance in <i>Aspergillus fumigatus<\/i>"],"prefix":"10.26508","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5194-9054","authenticated-orcid":true,"given":"Peter","family":"Hortschansky","sequence":"first","affiliation":[{"name":"Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), and Friedrich Schiller University Jena, Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Misslinger","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology\/Biocenter, Innsbruck Medical University, Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"M\u00f6rl","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology\/Biocenter, Innsbruck Medical University, Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Gsaller","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology\/Biocenter, Innsbruck Medical University, Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Bromley","sequence":"additional","affiliation":[{"name":"Manchester Fungal Infection Group, Institute of Inflammation and Repair, University of Manchester, 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