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This study found that in response to antifungal azole stress, <jats:italic>Neurospora crassa<\/jats:italic> could activate the transcriptional responses of many genes and increase azole resistance by reducing the level of conidial separation 1 (CSP-1), a global transcription repressor, at azole-responsive genes. The expression of <jats:italic>csp-1<\/jats:italic> was directly activated by the transcription factors WC-1 and WC-2. Upon ketoconazole (KTC) stress, the transcript levels of <jats:italic>wc-1<\/jats:italic> and <jats:italic>wc-2<\/jats:italic> were not changed, but <jats:italic>csp-1<\/jats:italic> transcription rapidly declined. A chromatin immunoprecipitation-quantitative polymerase chain reaction analysis revealed a rapid reduction in the WC-2 enrichment at the <jats:italic>csp-1<\/jats:italic> promoter upon KTC treatment, which might be responsible for the KTC-induced <jats:italic>csp-1<\/jats:italic> downregulation. Deletion of <jats:italic>csp-1<\/jats:italic> increased resistance to KTC and voriconazole, while <jats:italic>csp-1<\/jats:italic> overexpression increased KTC susceptibility. CSP-1 transcriptionally repressed a number of azole-responsive genes, including genes encoding the azole target ERG11, the azole efflux pump CDR4 and the sterol C-22 desaturase ERG5. Deletion of <jats:italic>csp-1<\/jats:italic> also reduced the KTC-induced accumulation of ergosterol intermediates, eburicol and 14\u03b1-methyl-3,6-diol. CSP-1 orthologs are widely present in filamentous fungi and an <jats:italic>Aspergillus fumigatus<\/jats:italic> mutant in which the <jats:italic>csp-1<\/jats:italic> was deleted was resistant to itraconazole.<\/jats:p>","DOI":"10.1038\/srep19447","type":"journal-article","created":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T11:03:16Z","timestamp":1453201396000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["De-repression of CSP-1 activates adaptive responses to antifungal azoles"],"prefix":"10.1038","volume":"6","author":[{"given":"Xi","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiping","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaojie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,1,19]]},"reference":[{"key":"BFsrep19447_CR1","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/S1471-4914(02)02280-3","volume":"8","author":"A Lupetti","year":"2002","unstructured":"Lupetti, A., Danesi, R., Campa, M., Tacca, M. 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