Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Biochemistry & Molecular Biology, Chemistry, Multidisciplinary, Chemistry, Polygodial, antifungal, Saccharomyces cerevisiae, haploid deletion mutant library, V-ATPase, vacuolar pH, ubiquitin, TORC1 signaling, Ca2+ signaling and Ca2+ homeostasis, CHRONOLOGICAL LIFE-SPAN, CA2+ HOMEOSTASIS, KEY REGULATOR, YEAST, SESQUITERPENE, COMPLEX, ATPASE, TORC1, ACIDIFICATION, UBIQUITIN, Antifungal Agents, Calcium, Drug Resistance, Fungal, Homeostasis, Hydrogen-Ion Concentration, Mechanistic Target of Rapamycin Complex 1, Microbial Sensitivity Tests, Mitochondria, Mitochondrial Proteins, Nucleosomes, Saccharomyces cerevisiae Proteins, Sesquiterpenes, Signal Transduction, Vacuolar Proton-Translocating ATPases, C14/17/063#54271136, 0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences, Chemical Physics, 3101 Biochemistry and cell biology, 3107 Microbiology, 3404 Medicinal and biomolecular chemistry

Abstract:

Polygodial is a "hot" peppery-tasting sesquiterpenoid that was first described for its anti-feedant activity against African armyworms. Using the haploid deletion mutant library of Saccharomyces cerevisiae, a genome-wide mutant screen was performed to shed more light on polygodial's antifungal mechanism of action. We identified 66 deletion strains that were hypersensitive and 47 that were highly resistant to polygodial treatment. Among the hypersensitive strains, an enrichment was found for genes required for vacuolar acidification, amino acid biosynthesis, nucleosome mobilization, the transcription mediator complex, autophagy and vesicular trafficking, while the resistant strains were enriched for genes encoding cytoskeleton-binding proteins, ribosomal proteins, mitochondrial matrix proteins, components of the heme activator protein (HAP) complex, and known regulators of the target of rapamycin complex 1 (TORC1) signaling. WE confirm that polygodial triggers a dose-dependent vacuolar alkalinization and that it increases Ca2+ influx and inhibits glucose-induced Ca2+ signaling. Moreover, we provide evidence suggesting that TORC1 signaling and its protective agent ubiquitin play a central role in polygodial resistance, suggesting that they can be targeted by polygodial either directly or via altered Ca2+ homeostasis.