title: De-repression of CSP-1 activates adaptive responses to antifungal azoles.
abstract: Antifungal azoles are the major drugs that are used to treat fungal infections. This study found that in response to antifungal azole stress, Neurospora crassa 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 csp-1 was directly activated by the transcription factors WC-1 and WC-2. Upon ketoconazole (KTC) stress, the transcript levels of wc-1 and wc-2 were not changed, but csp-1 transcription rapidly declined. A chromatin immunoprecipitation-quantitative polymerase chain reaction analysis revealed a rapid reduction in the WC-2 enrichment at the csp-1 promoter upon KTC treatment, which might be responsible for the KTC-induced csp-1 downregulation. Deletion of csp-1 increased resistance to KTC and voriconazole, while csp-1 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 csp-1 also reduced the KTC-induced accumulation of ergosterol intermediates, eburicol, and 14α-methyl-3,6-diol. CSP-1 orthologs are widely present in filamentous fungi, and an Aspergillus fumigatus mutant in which the csp-1 was deleted was resistant to itraconazole.
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xue
authors.affiliation: Technical Centre of Beijing Cigarette Factory, Beijing 101121, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhenying
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Marine Sciences, China University of Geosciences, Beijing 100083, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Wei
authors.affiliation: Technical Centre of Beijing Cigarette Factory, Beijing 101121, China.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xianyun
authors.initials: X
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Wenzhao
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Shaojie
authors.initials: S
authors.lastname: Li
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D001393:Azoles / Q000494:pharmacology*; D015536:Down-Regulation; D025141:Drug Resistance, Fungal; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D009492:Neurospora crassa / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014158:Transcription, Genetic
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins