title: First step of glycosylphosphatidylinositol (GPI) biosynthesis cross-talks with ergosterol biosynthesis and Ras signaling in Candida albicans.
abstract: Candida albicans is a leading cause of fungal infections worldwide. It has several glycosylphosphatidylinositol (GPI)-anchored virulence factors. Inhibiting GPI biosynthesis attenuates its virulence. Building on our previous work, we explore the interaction of GPI biosynthesis in C. albicans with ergosterol biosynthesis and hyphal morphogenesis. This study is also the first report of transcriptional co-regulation existing between two subunits of the multisubunit enzyme complex, GPI-N-acetylglucosaminyltransferase (GPI-GnT), involved in the first step of GPI anchor biosynthesis in eukaryotes. Using mutational analysis, we show that the accessory subunits, GPI2 and GPI19, of GPI-GnT exhibit opposite effects on ergosterol biosynthesis and Ras signaling (which determines hyphal morphogenesis). This is because the two subunits negatively regulate one another; GPI19 mutants show up-regulation of GPI2, whereas GPI2 mutants show up-regulation of GPI19. Two different models were examined as follows. First, the two GPI-GnT subunits independently interact with ergosterol biosynthesis and Ras signaling. Second, the two subunits mutually regulate one another and thereby regulate sterol levels and Ras signaling. Analysis of double mutants of these subunits indicates that GPI19 controls ergosterol biosynthesis through ERG11 levels, whereas GPI2 determines the filamentation by cross-talk with Ras1 signaling. Taken together, this suggests that the first step of GPI biosynthesis talks to and regulates two very important pathways in C. albicans. This could have implications for designing new antifungal strategies.
authors.affiliation: From the School of Life Sciences, Jawaharlal Nehru University, New Delhi 110 067, India.
authors.forename: Bhawna
authors.initials: B
authors.lastname: Yadav
authors.forename: Shilpi
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Mohammad Faiz
authors.initials: MF
authors.lastname: Ahmad
authors.forename: Priyanka
authors.initials: P
authors.lastname: Jain
authors.forename: Vavilala A
authors.initials: VA
authors.lastname: Pratyusha
authors.forename: Pravin
authors.initials: P
authors.lastname: Kumar
authors.forename: Sneha Sudha
authors.initials: SS
authors.lastname: Komath
mesh_terms: D002176:Candida albicans / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004875:Ergosterol / Q000096:biosynthesis* / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D005656:Fungal Proteins; D017261:Glycosylphosphatidylinositols; D003577:Cytochrome P-450 Enzyme System; D005964:Glucosyltransferases; D016283:Proto-Oncogene Proteins p21(ras); D004875:Ergosterol
keywords: Candida albicans; Ergosterol Biosynthesis; Filamentation; Fungi; GPI-N-Acetylglucosaminyltransferase Complex; Glycosylphosphatidyl Anchor Biosynthesis; Molecular Cell Biology; Ras; Ras Signaling; Sterol