The δ subunit of F(1)F(o)-ATP synthase is required for pathogenicity of Candida albicans.
The δ subunit of F(1)F(o)-ATP synthase is required for pathogenicity of Candida albicans.
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F1Fo-ATP 合酶的 δ 亚基是白色念珠菌致病性所必需的
DOI：
10.1038/s41467-021-26313-9
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发表时间：
2021-10-15
影响因子：
16.6
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Li S;Zhao Y;Zhang Y;Zhang Y;Zhang Z;Tang C;Weng L;Chen X;Zhang G;Zhang H
真菌感染，特别是念珠菌病和曲霉病，致死率很高。真菌细胞的生长和功能需要ATP，ATP主要通过氧化磷酸化合成，其中关键酶是F1 Fo-ATP合酶。在这里，我们表明，删除白色念珠菌基因编码的F1 Fo-ATP合酶（ATP 16）的δ亚基废除致死性感染的小鼠模型系统性念珠菌病。该缺失基本上不影响体外真菌生长或细胞内ATP浓度，因为氧化磷酸化衍生的ATP合成的减少被增强的糖酵解补偿。然而，ATP 1,6缺失突变体显示磷酸果糖激酶活性降低，导致果糖1，6-二磷酸水平降低，Ras 1依赖性和非依赖性cAMP-PKA途径活性降低，毒力因子下调，致病性降低。小分子的基于结构的虚拟筛选导致鉴定潜在靶向真菌F1 Fo-ATP酶δ亚基的化合物。该化合物诱导的体外表型与在ATP 16缺失突变体中观察到的表型相似，并保护小鼠免于感染侵袭性念珠菌病。我们的研究结果表明，F1 Fo-ATP合酶δ亚基是C.白色念珠菌致死性感染，代表了潜在的治疗靶点。F1 Fo-ATP合成酶是真菌能量产生的关键酶。在这里，作者表明该酶的δ亚基是白色念珠菌致死感染所必需的，并且代表了潜在的治疗靶点。
Fungal infections, especially candidiasis and aspergillosis, claim a high fatality rate. Fungal cell growth and function requires ATP, which is synthesized mainly through oxidative phosphorylation, with the key enzyme being F1Fo-ATP synthase. Here, we show that deletion of the Candida albicans gene encoding the δ subunit of the F1Fo-ATP synthase (ATP16) abrogates lethal infection in a mouse model of systemic candidiasis. The deletion does not substantially affect in vitro fungal growth or intracellular ATP concentrations, because the decrease in oxidative phosphorylation-derived ATP synthesis is compensated by enhanced glycolysis. However, the ATP16-deleted mutant displays decreased phosphofructokinase activity, leading to low fructose 1,6-bisphosphate levels, reduced activity of Ras1-dependent and -independent cAMP-PKA pathways, downregulation of virulence factors, and reduced pathogenicity. A structure-based virtual screening of small molecules leads to identification of a compound potentially targeting the δ subunit of fungal F1Fo-ATP synthases. The compound induces in vitro phenotypes similar to those observed in the ATP16-deleted mutant, and protects mice from succumbing to invasive candidiasis. Our findings indicate that F1Fo-ATP synthase δ subunit is required for C. albicans lethal infection and represents a potential therapeutic target. F1Fo-ATP synthase is a key enzyme for energy production in fungi. Here, the authors show that the δ subunit of the enzyme is required for Candida albicans lethal infection and represents a potential therapeutic target.
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影响因子：
64.5
作者：
Lo, HJ;Kohler, JR;Fink, GR
通讯作者：
Fink, GR
DOI：
10.1098/rstb.2015.0468
发表时间：
2016-12-05
影响因子：
6.3
作者：
Denning，David W.
通讯作者：
Denning，David W.
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
6.7
作者：
Grahl N;Demers EG;Lindsay AK;Harty CE;Willger SD;Piispanen AE;Hogan DA
通讯作者：
Hogan DA
FUS 与 ATP 合酶 β 亚基相互作用并在细胞和动物模型中诱导线粒体未折叠蛋白反应
DOI：
10.1073/pnas.1806655115
发表时间：
2018-10-09
影响因子：
11.1
作者：
Deng, Jianwen;Wang, Peng;Wu, Jane Y.
通讯作者：
Wu, Jane Y.