title: The Phosphoinositide 3-Kinase Regulates Retrograde Trafficking of the Iron Permease CgFtr1 and Iron Homeostasis in Candida glabrata.
abstract: The phosphoinositide 3-kinase (PI3K), which phosphorylates phosphatidylinositol and produces PI3P, has been implicated in protein trafficking, intracellular survival, and virulence in the pathogenic yeast Candida glabrata Here, we demonstrate PI3-kinase (CgVps34) to be essential for maintenance of cellular iron homeostasis. We examine how CgVps34 regulates the fundamental process of iron acquisition, and underscore its function in vesicular trafficking as a central determinant. RNA sequencing analysis revealed iron homeostasis genes to be differentially expressed upon CgVps34 disruption. Consistently, the Cgvps34Δ mutant displayed growth attenuation in low- and high-iron media, increased intracellular iron content, elevated mitochondrial aconitase activity, impaired biofilm formation, and extenuated mouse organ colonization potential. Furthermore, we demonstrate for the first time that C. glabrata cells respond to iron limitation by expressing the iron permease CgFtr1 primarily on the cell membrane, and to iron excess via internalization of the plasma membrane-localized CgFtr1 to the vacuole. Our data show that CgVps34 is essential for the latter process. We also report that macrophage-internalized C. glabrata cells express CgFtr1 on the cell membrane indicative of an iron-restricted macrophage internal milieu, and Cgvps34Δ cells display better survival in iron-enriched medium-cultured macrophages. Overall, our data reveal the centrality of PI3K signaling in iron metabolism and host colonization.
authors.affiliation: From the Centre for DNA Fingerprinting and Diagnostics, Survey Nos. 728, 729, 730 and 734, Opposite Uppal Water Tank, Beside BSNL T E Building, Uppal, Hyderabad 500039, Ranga Reddy District, India and; the Graduate Studies, Manipal University, Manipal, India.
authors.forename: Vandana
authors.initials: V
authors.lastname: Sharma
authors.affiliation: From the Centre for DNA Fingerprinting and Diagnostics, Survey Nos. 728, 729, 730 and 734, Opposite Uppal Water Tank, Beside BSNL T E Building, Uppal, Hyderabad 500039, Ranga Reddy District, India and.
authors.forename: Rajaram
authors.initials: R
authors.lastname: Purushotham
authors.affiliation: From the Centre for DNA Fingerprinting and Diagnostics, Survey Nos. 728, 729, 730 and 734, Opposite Uppal Water Tank, Beside BSNL T E Building, Uppal, Hyderabad 500039, Ranga Reddy District, India and. Electronic address: rkaur@cdfd.org.in.
authors.forename: Rupinder
authors.initials: R
authors.lastname: Kaur
mesh_terms: D000818:Animals; D041221:Candida glabrata / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D002177:Candidiasis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D005656:Fungal Proteins; D007501:Iron; D026901:Membrane Transport Proteins; D019869:Phosphatidylinositol 3-Kinases
keywords: Ftr1-Fet3 complex; biofilm; fungi; intracellular and mitochondrial iron levels; iron metabolism; lipid kinase Vps34; microbial pathogenesis; pathogenic yeasts; phosphatidylinositide 3-kinase (PI 3-kinase)