The Phosphoinositide 3-Kinase Regulates Retrograde Trafficking of the Iron Permease CgFtr1 and Iron Homeostasis in Candida glabrata

Abstract

Edited by James SiedowThe 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 Cgvps34⌬ 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 Cgvps34⌬ 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.

An iron-dependent metabolic vulnerability underlies VPS34-dependence in RKO cancer cells

“…Interestingly, a role for VPS34 in iron homeostasis has also been described in the yeast Candida glabrata [59]. In C. glabrata, CgVPS34 regulates iron homeostasis by controlling the retrograde trafficking of CgFtr1, a high-affinity iron transporter, through the endosomal pathway.…”

“…Interestingly, a role for VPS34 in iron homeostasis has also been described in the yeast Candida glabrata [ 59 ]. In C .…”

Meeting report – the Microtubules, Motors, Transport and Trafficking (M2T2) 2019 meeting

“…Rupinder Kaur (Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India) started the first session on this theme with a discussion of the role for phosphoinositide 3-kinase (PI3K) in the vesicular trafficking and pathogenesis of Candida glabrata. Her talk implicated C. glabrata (Cg)Vps34 in the vesicular trafficking, autophagy, iron homeostasis, biofilm formation and virulence of the organism, in addition to retrograde trafficking of metal ion transporters from the plasma membrane in response to environmental cues (Sharma et al, 2016).…”

Iron acquisition in fungal pathogens of humans

“…45 An ortholog of the FTR1 -encoded iron permease was identified in C. glabrata and found to be required for growth in iron-restricted medium. 37,46 Additionally, deletion of FTR1 caused reduced colonization of the kidneys of infected mice suggesting that the iron permease is essential for the virulence of C. glabrata . 37 The same study also identified the C. glabrata ortholog of the Fet3 ferroxidase of S. cerevisiae .…”

“…37 Interestingly, plasma membrane-localized Ftr1 moves to the vacuole in a Vps34-dependent manner upon exposure of C. glabrata to excess iron. 46 VPS34 encodes a phosphoinositide 3-kinase, and the C. glabrata mutant lacking the gene shows impaired iron homeostasis and a significant reduction of organ colonization in mice. The inability of a vps34 mutant to properly traffic Ftr1 as well as other virulence-related phenotypes ( e.g.…”