The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum
The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum
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DOI：
10.1093/jac/dkm321
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发表时间：
2007-12-01
影响因子：
5.2
通讯作者：
Niimi, Masakazu
中科院分区：
文献类型：
--
作者：
Nakayama, Hironobu;Tanabe, Koichi;Niimi, Masakazu
目的：从血清中摄取内源性甾醇可能使光滑念珠菌在唑治疗后存活。本研究的目的是确定在血清存在下改变氟康唑敏感性的固醇转运蛋白的贡献。glabrata是酿酒酵母转运蛋白AUS 1和PDR 11的直向同源物。为了研究CgAUS 1基因是否具有固醇转运蛋白活性，我们研究了AUS 1缺失对四环素可调控的ERG 9菌株（tet-ERG 9aus 1）生长的影响，其中ERG 9表达被关闭，从而产生固醇需求。四环素依赖性阻遏的CgAUS 1在tet-AUS 1菌株被用来确定氟康唑的敏感性CgAUS 1在存在和不存在的serum.Results：四环素处理的tet-ERG 9aus 1菌株不能生长在血清的存在下，而亲本tet-ERG 9AUS 1菌株生长通过掺入甾醇从外源性提供的血清。血清胆固醇保护细胞对抗氟康唑的抗真菌作用，这种保护作用通过抑制CgAUS 1基因表达而丧失。此外，这样的保护也观察到伊曲康唑治疗期间，但没有观察到在细胞治疗与non-azole antifungals.Conclusions：CgAUS 1出现作为一个甾醇转运蛋白，可能有助于降低唑敏感性的存在下，血清和保护C。glabrata对抗唑类药物的体内毒性。
Objectives: The uptake of endogenous sterol from serum may allow Candida glabrata to survive azole treatment. This study aims to determine the contribution of a sterol transporter that alters fluconazole sensitivity in the presence of serum.Methods: Bioinformatic analysis predicted CgAUS1 as the C. glabrata orthologue of the Saccharomyces cerevisiae transporters AUS1 and PDR11. To investigate whether the CgAUS1 gene has sterol transporter activity, we investigated the effects of an AUS1 deletion on the growth of a tetracycline-regulatable ERG9 strain (tet-ERG9aus1), wherein ERG9 expression is turned off giving rise to a sterol requirement. Tetracycline-dependent repression of CgAUS1 in the tet-AUS1 strain was used to determine the fluconazole susceptibility of CgAUS1 in the presence and absence of serum.Results: The tetracycline-treated tet-ERG9aus1 strain failed to grow in the presence of serum, whereas the parental tet-ERG9AUS1 strain grew by incorporating sterol from exogenously supplied serum. Serum cholesterol protected cells against the antifungal effects of fluconazole and this protection was lost by repressing CgAUS1 gene expression. Furthermore, such protection was also observed during itraconazole treatment, but not observed in cells treated with non-azole antifungals.Conclusions: CgAUS1 appears to function as a sterol transporter that may contribute to lower azole susceptibility in the presence of serum and to protect C. glabrata against azole toxicity in vivo.