Sugar Sensing and Signaling in Candida albicans and Candida glabrata

Abstract

Candida species, such as Candida albicans and Candida glabrata, cause infections at different host sites because they adapt their metabolism depending on the available nutrients. They are able to proliferate under both nutrient-rich and nutrient-poor conditions. This adaptation is what makes these fungi successful pathogens. For both species, sugars are very important nutrients and as the sugar level differs depending on the host niche, different sugar sensing systems must be present. Saccharomyces cerevisiae has been used as a model for the identification of these sugar sensing systems. One of the main carbon sources for yeast is glucose, for which three different pathways have been described. First, two transporter-like proteins, ScSnf3 and ScRgt2, sense glucose levels resulting in the induction of different hexose transporter genes. This situation is comparable in C. albicans and C. glabrata, where sensing of glucose by CaHgt4 and CgSnf3, respectively, also results in hexose transporter gene induction. The second glucose sensing mechanism in S. cerevisiae is via the G-protein coupled receptor ScGpr1, which causes the activation of the cAMP/PKA pathway, resulting in rapid adaptation to the presence of glucose. The main components of this glucose sensing system are also conserved in C. albicans and C. glabrata. However, it seems that the ligand(s) for CaGpr1 are not sugars but lactate and methionine. In C. glabrata, this pathway has not yet been investigated. Finally, the glucose repression pathway ensures repression of respiration and repression of the use of alternative carbon sources. This pathway is not well characterized in Candida species. It is important to note that, apart from glucose, other sugars and sugar-analogs, such as N-acetylglucosamine in the case of C. albicans, are also important carbon sources. In these fungal pathogens, sensing sugars is important for a number of virulence attributes, including adhesion, oxidative stress resistance, biofilm formation, morphogenesis, invasion, and antifungal drug tolerance. In this review, the sugar sensing and signaling mechanisms in these Candida species are compared to S. cerevisiae.

Keywords: Candida albicans; Candida glabrata; Gpr1/Gpa2; Saccharomyces cerevisiae; Snf1/Mig1; Snf3/Rgt2-Hgt4; sugar sensing; sugar transport.

Figure 1

Sugar concentrations in the human body. This figure shows the sugar concentrations at the different infection sites of the Candida species. These pathogens are present at different sites of the human host, namely, in the mouth, in the gut, in the vagina, in the blood, and on the skin (Sone et al., 2003; Ehrstrom et al., 2006; Groenendaal et al., 2010; Laughlin, 2014). This figure is adapted from the review of Gulati and Nobile (2016). Permission was given to reuse this figure.

Figure 2

Sugar sensing and signaling in S. cerevisiae. The sugar-sensing network in S. cerevisiae. The faded arrows and proteins represent the situation when sugars are absent. All proteins are represented as circles. Activation is represented with green arrows, while red arrows indicate inhibition. When the ScSnf3/ScRgt2 receptors sense glucose, ScYck1 phosphorylates ScStd1 and ScMth1. These are subsequently ubiquitinated by ScGrr1 and broken down by the proteasome. In the absence of glucose, they function together with ScRgt1 to repress transcription of the ScHXT genes. The ScHxt transporters allow glucose to enter the cells after which this monosaccharide is converted to pyruvate during glycolysis. One of the intermediates of this pathway is fructose 1,6 bisphosphate which is found to activate ScCdc25. In this way, ScCdc25 allows the exchange of GDP to GTP on the ScRas proteins. ScRas is now activated and stimulates ScCyr1. Next to activation by ScRas, ScCyr1 needs the stimulus coming from ScGpr1 to be fully activated. ScGpr1 is activated by sensing extracellular glucose which allows the exchange of GDP to GTP on the ScGpa2 proteins. ScGpa2-GTP activates ScCyr1. ATP is converted into cAMP after complete activation of ScCyr1. cAMP binds to the regulatory subunits of PKA (Bcy1) thereby causing them to release the catalytic subunits (ScTpk1, 2, and 3) causing PKA activation. The absence of glucose triggers the phosphorylation of ScSnf1 by ScSak1, ScElm1, and ScTos3. The activated ScSnf1 protein phosphorylates ScMig1, preventing this protein to enter the nucleus. In the presence of glucose, both ScSnf1 and ScMig1 are dephosphorylated by ScReg1, allowing ScMig1 to enter the nucleus and function as a transcriptional repressor of the ScGAL genes and ScMTH1. When galactose is present (in the absence of glucose), it can enter the cells via the ScGal2 permease. Galactose can bind to ScGal3, which sequesters ScGal80 and prevents the latter to bind ScGal4. ScGal4 can thereby actively function in the nucleus as a transcription factor, inducing the expression of the ScGAL genes and of ScMTH1.

Figure 3

Sugar sensing and signaling in C. albicans. The sugar-sensing network in C. albicans. The faded arrows and proteins represent the situation when sugars are absent. All proteins are represented as circles. Activation is represented with green arrows, while red arrows indicate inhibition. The dashed lines represent the hypothesis. When the CaHgt4 receptor senses glucose, galactose, maltose, or fructose, CaYck2 phosphorylates CaStd1. This is subsequently ubiquitinated by CaGrr1 and broken down by the proteasome. In the absence of a carbon source, CaStd1 functions together with CaRgt1 to repress transcription of the CaHGT genes. The CaHgt transporters allow sugars to enter the cells. When glucose enters the cells, it is converted to pyruvate during glycolysis. In the presence of extracellular glucose, an active CaCdc25 allows the exchange of GDP to GTP on the CaRas proteins. CaRas is now activated and stimulates CaCyr1. Next to activation by CaRas, CaCyr1 needs the stimulus coming from CaGpr1 to be fully activated. CaGpr1 is activated by sensing extracellular molecules, presumably methionine or lactate, which allows the exchange of GDP to GTP on the CaGpa2 proteins. CaGpa2-GTP activates CaCyr1. ATP is converted into cAMP after complete activation of CaCyr1 by CaRas and by CaGpa2. cAMP binds to the regulatory subunits of PKA (CaBcy1) thereby causing them to release the catalytic subunits (CaTpk) causing PKA activation. When N-acetylglucosamine enters the cells via CaNgt1, it can be metabolized to fructose-6-phosphate by CaHxk1, CaDac1, and CaNag1. The hypothesis is that fructose-6-phosphate can be converted into galactose by the action of the CaGal enzymes. The galactose metabolism in C. albicans remains a mystery, but the expression of the CaGAL genes is found to be regulated by CaCph1 and CaRgt1. CaSnf1 can be phosphorylated by CaSak1 but no more in this pathway has been revealed.

Figure 4

Sugar sensing and signaling in C. glabrata. The sugar-sensing network in C. glabrata. The faded arrows and proteins represent the situation when sugars are absent. All proteins are represented as circles. Activation is represented with green arrows, while red arrows indicate inhibition. When the CgSnf3/CgRgt2 receptors sense glucose CgYck1 phosphorylates CgStd1. This is subsequently ubiquitinated by CgGrr1 and broken down by the proteasome. In the absence of glucose, CgStd1 functions together with CgRgt1 to repress transcription of the CgHXT genes. The CgHxt transporters allow glucose to enter the cells.