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F1Fo-ATP synthase subunit determines lethal pathogenic fungi infection

ABSTRACT: Fungal infections, especially candidiasis and aspergillosis, claim an unacceptably high fatality rate. The energy ATP that is necessary for fungal cell growth and function is synthesized mainly through oxidative phosphorylation, with the key enzyme being F1Fo-ATP synthase. But it remains unknown how this enzyme affects fungal pathogenicity. Here, we show that F1Fo-ATP synthase δ subunit deletion abrogates lethal Candida albicans infection without affecting intracellular ATP concentrations or growth. Mechanistically, δ subunit deletion reduces Pfk1 activity by interrupting Pfk1 phosphorylation to trigger its conformation shifts, decreases downstream FBP level, blocks Ras1-dependent and -independent cAMP-PKA pathways, and curtails virulence factors. Based on these findings, we engineer a small molecule compound targeting δ subunit that effectively protects mice from succumbing to invasive candidiasis. In summary, our findings reveal that F1Fo-ATP synthase δ subunit determines lethal infection from pathogenic fungi and represents a potential therapeutic target.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic

SUBMITTER: æ°´ç§ æ

PROVIDER: MTBLS3332 | MetaboLights | 2021-10-08

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS3332	Other
	FILES	Other
	a_MTBLS3332_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	files-all.json	Other
	i_Investigation.txt	Txt

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F1Fo-ATP synthase subunit determines lethal infection in pathogenic fungi

Project description:Fungal infections, especially for candidiasis and aspergillosis, claim an unacceptably high fatality. However, the determining mechanism that promote fungal lethal infections are still elusive. The energy ATP necessary for fungal cell growth and function is synthesized mainly through oxidative phosphorylation, whose key enzyme is F1Fo-ATP synthase. Nonetheless, it remians unknown how this enzyme affects fungal pathogenicity. Here we show that F1Fo-ATP synthase subunit deletion completely abrogates C. albicans lethal infection rather than leading to remarkable intracellular ATP concentration and growth defect. Mechanically, subunit deletion reduces PFK1 activity via interrupting PFK1 phosphorylation to trigger its conformational change, decreases downstream FBP level, blocks Ras1-dependent and -independent cAMP-PKA pathway, and curtails virulence factors. Based on these findings, we engineer a small molecule compound aimed at subunit that effectively protects mice from succumbing to invasive candidiasis. In summary, our findings reveal that F1Fo-ATP synthase δ subunit determines the lethal infection of pathogenic fungi and represents a potential new therapeutic target.

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