Calcineurin-dependent contributions to fitness in the opportunistic pathogen Candida glabrata.
Calcineurin-dependent contributions to fitness in the opportunistic pathogen Candida glabrata.
复制标题
钙调磷酸酶对条件致病菌光假丝酵母适应性的影响。
作者：
蛋白磷酸酶钙调神经磷酸酶对于光滑假丝酵母的致病性至关重要。激活钙调磷酸酶信号传导的宿主诱导的应激是未知的，与毒力相关的钙调磷酸酶的靶点也是未知的。为了阐明这些过程，我们对C. glabrata的适应性缺陷的存在下，FK506，钙调神经磷酸酶的特异性抑制剂进行了分析。87个特异性基因缺陷依赖于钙调磷酸酶信号传导，在缺乏多效性耐药的野生型和pdr1基因缺失菌株中体外完全存活。参与细胞壁生物合成的三个基因（FKS1，DCW1，FLC1）具有共同必需的旁系同源物，其表达依赖于钙调磷酸酶和Crz1，以响应米卡芬净，一种干扰细胞壁生物合成的临床抗真菌剂。有趣的是，80%的FK506敏感突变体在囊泡运输的不同方面存在缺陷，如内质网（ER）中分泌蛋白的内吞作用、胞吐作用、分选和生物合成。为了响应阻断ER中GPI锚生物合成的实验性抗真菌剂manogepix，钙调磷酸酶信号传导增加并强烈阻止细胞死亡，而不依赖于其主要靶点之一Crz1。Manogepix、米卡芬净和ER应激衣霉素之间的比较揭示了钙调磷酸酶信号传导程度与细胞存活程度之间的相关性。这些发现表明，钙调神经磷酸酶在减轻囊泡运输的压力中起着重要作用。这种压力可能会出现在宿主感染和抗真菌治疗的反应。钙调神经磷酸酶在大多数病原真菌的毒力中起关键作用。这项研究揭示了这些作用的机会致病菌光滑念珠菌使用全基因组分析体外。这一发现可能导致抗真菌药物的发展，也避免了免疫抑制。
The protein phosphatase calcineurin is vital for the virulence of the opportunistic fungal pathogen Candida glabrata. The host-induced stresses that activate calcineurin signaling are unknown, as are the targets of calcineurin relevant to virulence. To potentially shed light on these processes, millions of transposon insertion mutants throughout the genome of C. glabrata were profiled en masse for fitness defects in the presence of FK506, a specific inhibitor of calcineurin. Eighty-seven specific gene deficiencies depended on calcineurin signaling for full viability in vitro both in wild-type and pdr1∆ null strains lacking pleiotropic drug resistance. Three genes involved in cell wall biosynthesis (FKS1, DCW1, FLC1) possess co-essential paralogs whose expression depended on calcineurin and Crz1 in response to micafungin, a clinical antifungal that interferes with cell wall biogenesis. Interestingly, 80% of the FK506-sensitive mutants were deficient in different aspects of vesicular trafficking, such as endocytosis, exocytosis, sorting, and biogenesis of secretory proteins in the endoplasmic reticulum (ER). In response to the experimental antifungal manogepix that blocks GPI-anchor biosynthesis in the ER, calcineurin signaling increased and strongly prevented cell death independent of Crz1, one of its major targets. Comparisons between manogepix, micafungin, and the ER-stressing tunicamycin reveal a correlation between the degree of calcineurin signaling and the degree of cell survival. These findings suggest that calcineurin plays major roles in mitigating stresses of vesicular trafficking. Such stresses may arise during host infection and in response to antifungal therapies. Calcineurin plays critical roles in the virulence of most pathogenic fungi. This study sheds light on those roles in the opportunistic pathogen Candida glabrata using a genome-wide analysis in vitro. The findings could lead to antifungal developments that also avoid immunosuppression.
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DOI：
10.3390/jof8101102
发表时间：
2022-10-19
期刊：
Journal of fungi (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1093/jac/dkab454
发表时间：
2022-02-23
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
--
作者：
Ceballos-Garzon A;Monteoliva L;Gil C;Alvarez-Moreno C;Vega-Vela NE;Engelthaler DM;Bowers J;Le Pape P;Parra-Giraldo CM
通讯作者：
Parra-Giraldo CM
影响因子：
5.3
作者：
CYERT, MS;THORNER, J
通讯作者：
THORNER, J
影响因子：
6.7
作者：
Hoepfner, Dominic;Helliwell, Stephen B.;Movva, N. Rao
通讯作者：
Movva, N. Rao
DOI：
10.1534/g3.112.002279
发表时间：
2012-06
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Chen YL;Konieczka JH;Springer DJ;Bowen SE;Zhang J;Silao FG;Bungay AA;Bigol UG;Nicolas MG;Abraham SN;Thompson DA;Regev A;Heitman J
通讯作者：
Heitman J