The δ subunit of F1Fo-ATP synthase is required for pathogenicity of Candida albicans

Author:

Li Shuixiu,Zhao Yajing,Zhang Yishan,Zhang Yanli,Zhang Zhanpeng,Tang Chuanyan,Weng Luobei,Chen Xiaohong,Zhang GehuaORCID,Zhang HongORCID

Abstract

AbstractFungal 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.

Funder

China Postdoctoral Science Foundation

National Natural Science Foundation of China

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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