A Glucose Sensor in Candida albicans

Abstract

The Hgt4 protein of Candida albicans (orf19.5962) is orthologous to the Snf3 and Rgt2 glucose sensors of Saccharomyces cerevisiae that govern sugar acquisition by regulating the expression of genes encoding hexose transporters. We found that HGT4 is required for glucose induction of the expression of HGT12, HXT10, and HGT7, which encode apparent hexose transporters in C. albicans. An hgt4⌬ mutant is defective for growth on fermentable sugars, which is consistent with the idea that Hgt4 is a sensor of glucose and similar sugars. Hgt4 appears to be sensitive to glucose levels similar to those in human serum (ϳ5 mM). HGT4 expression is repressed by high levels of glucose, which is consistent with the idea that it encodes a high-affinity sugar sensor. Glucose sensing through Hgt4 affects the yeast-to-hyphal morphological switch of C. albicans cells: hgt4⌬ mutants are hypofilamented, and a constitutively signaling form of Hgt4 confers hyperfilamentation of cells. The hgt4⌬ mutant is less virulent than wild-type cells in a mouse model of disseminated candidiasis. These results suggest that Hgt4 is a high-affinity glucose sensor that contributes to the virulence of C. albicans.Candida albicans is responsible for most yeast infections in humans. In addition to causing ordinary vaginal and oral (thrush) infections, this fungus is a serious threat to immunocompromised patients, for whom disseminated, invasive candidiasis is common and often fatal (31, 56). The fungus is normally maintained as a harmless commensal on skin, on mucosa, and in the gut (23) but becomes an opportunistic pathogen upon entry into the bloodstream of immunocompromised (particularly neutropenic) individuals (25,45).

Asymmetric Signal Transduction through Paralogs That Comprise a Genetic Switch for Sugar Sensing in Saccharomyces cerevisiae

“…In a cell expressing both sensors, half of the Mth1 is depleted at ϳ0.05% glucose (2.75 mM), whereas in a strain lacking the high affinity glucose sensor (Snf3), a higher concentration of glucose, ϳ0.5%, is necessary to induce degradation of Mth1 to the same extent. Sensitivity at such a low glucose level is similar to that reported for the high affinity glucose sensor of Candida albicans (21). Interestingly, glucose levels higher than FIGURE 2.…”

“…Nutrient detection through transporter-like sensors is an ancient, unique mechanism by which yeast cells monitor their environment (21,44,45). The glucose sensor-dependent regulation of Mth1 level enables yeast cells to respond quickly to glucose over a wide range of concentrations.…”

“…The cell pellets were snap-frozen in liquid nitrogen and stored at Ϫ80°C. Total RNA was prepared as described (21) by extraction with hot phenol and chloroform, followed by isopropanol precipitation and reconstitution in TE buffer (10 mM Tris, pH 7.5, 1 mM EDTA). Fluorescent labeling, hybridization, and quantification were performed by the microarray core in the Genome Center at Washington University in St. Louis as previously described (22).…”

Prion-Forming Ability of Ure2 of Yeasts Is Not Evolutionarily Conserved

“…S. cerevisiae microarrays were purchased from Agilent. For C. glabrata, Agilent custom microarrays were used as described (Tsai et al 2010) C. albicans microarrys (Brown et al 2006) were purchased from the Genome Tsai et al (2010). Statistical calculations were performed on the processed signal data by using the mAdb analysis system provided by the BIMAS group at the Center for Information Technology, NIH.…”

Cap2-HAP Complex Is a Critical Transcriptional Regulator That Has Dual but Contrasting Roles in Regulation of Iron Homeostasis in Candida albicans

“…To identify Cap2-regulated genes, we carried out transcriptome profiling (66, 67) using the C. albicans whole genome microarray (50). We compared the mRNA profiles of wild-type and cap2⌬ cells cultured in BPS-containing medium and identified 420 up-regulated and 509 down-regulated genes (total 15.8% of the ORFs examined) that showed statistically significant differential expression (supplemental Table S5).…”