Transcription factor ADS-4 regulates adaptive responses and resistance to antifungal azole stress----中国科学院微生物研究所

科研成果

论文题目:	Transcription factor ADS-4 regulates adaptive responses and resistance to antifungal azole stress
作者:	Wang Kangji, Zhang Zhenying, Chen Xi, Sun Xianyun, Jin Cheng, Liu Hongwei*, and Li Shaojie.
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刊物名称:	Antimicrob Agents Chemother
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年份:	2015
影响因子:	4.54
论文下载:	http://aac.asm.org/content/early/2015/06/16/AAC.00542-15
摘要:	Azoles are commonly used as antifungal drugs or pesticides to control fungal infections in medicine and agriculture. Fungi adapt to azole stress by rapidly activating the transcription of a number of genes and transcriptional increases in some azole responsive genes can elevate azole resistance. The regulatory mechanisms that control transcriptional responses to azole stress are not well understood in filamentous fungi. This study identified a bZIP transcription factor, ADS-4 (antifungal drug sensitive-4), as a new regulator of adaptive responses and resistance to antifungal azoles. Transcription of ads-4 in Neurospora crassa increased when it was subjected to ketoconazole treatment, whereas the deletion of ads-4 resulted in hypersensitivity to ketoconazole and fluconazole. In contrast, the overexpression of ads-4 increased resistance to fluconazole and ketoconazole in N. crassa. RNA-seq, followed by qRT-PCR confirmation, showed that ADS-4 positively regulated the transcriptional responses of at least six genes to ketoconazole stress in N. crassa. The gene products of four ADS-4-regulated genes are known contributors to azole resistance, including the major efflux pump CDR4 (Pdr5p ortholog), an ABC multidrug transporter (NcAbcB), sterol C-22 desaturase ERG5 and a lipid transporter NcRTA2, which is involved in calcineurin-mediated azole resistance. Deletion of the ads-4 homologous gene Afads-4 in Aspergillus fumigatus caused hypersensitivity to itraconazole and ketoconazole, which suggested that ADS-4 is a functionally conserved regulator of adaptive responses to azoles. This study provides important information on a new azole resistance factor that could be targeted by a new range of anti-fungal pesticides and drugs.