Glycerophosphocholine provision rescues Candida albicans growth and signaling phenotypes associated with phosphate limitation

Abstract

ABSTRACTThe fungal pathogen Candida albicans must acquire phosphate to colonize, infect, and proliferate in the human host. C. albicans has four inorganic phosphate (Pi) transporters, Pho84 being the major high-affinity transporter; its cells can also use glycerophosphocholine (GPC) as their sole phosphate source. GPC is a lipid metabolite derived from deacylation of the lipid phosphatidylcholine. GPC is found in multiple human tissues, including the renal medulla, where it acts as an osmolyte. C. albicans imports GPC into the cell via the Git3 and Git4 transporters. Internalized GPC can be hydrolyzed to release Pi. To determine if GPC import and subsequent metabolism affect phosphate homeostasis upon Pi limitation, we monitored growth and phenotypic outputs in cells provided with either Pi or GPC. In pho84∆/∆ mutant cells that exhibit phenotypes associated with Pi limitation, GPC provision rescued sensitivity to osmotic and cell wall stresses. The glycerophosphodiesterase Gde1 was required for phenotypic rescue of osmotic stress by GPC provision. GPC provision, like Pi provision, resulted in repression of the PHO regulon and activation of TORC1 signaling. Pi uptake was similar to GPC uptake when phosphate availability was low (200 µM). While available at lower concentrations than Pi in the human host, GPC is an advantageous Pi source for the fungus because it simultaneously serves as a choline source. In summary, we find GPC is capable of substituting for Pi in C. albicans by many though not all criteria and may contribute to phosphate availability for the fungus in the human host.IMPORTANCECandida albicans is the most commonly isolated species from patients suffering from invasive fungal disease. C. albicans is most commonly a commensal organism colonizing a variety of niches in the human host. The fungus must compete for resources with the host flora to acquire essential nutrients such as phosphate. Phosphate acquisition and homeostasis have been shown to play a key role in C. albicans virulence, with several genes involved in these processes being required for normal virulence and several being upregulated during infection. In addition to inorganic phosphate (Pi), C. albicans can utilize the lipid-derived metabolite glycerophosphocholine (GPC) as a phosphate source. As GPC is available within the human host, we examined the role of GPC in phosphate homeostasis in C. albicans. We find that GPC can substitute for Pi by many though not all criteria and is likely a relevant physiological phosphate source for C. albicans.

Keywords

• phosphate metabolism
• phospholipids
• Candida albicans
• glycerophosphodiesters
• phosphate
• cell signaling