Hexokinase and Glucokinases Are Essential for Fitness and Virulence in the Pathogenic Yeast Candida albicans

Abstract

The pathogenic yeast Candida albicans is both a powerful commensal and a pathogen of humans that can infect wide range of organs and body sites. Metabolic flexibility promotes infection and commensal colonization by this opportunistic pathogen. Yeast cell survival depends upon assimilation of fermentable and non-fermentable locally available carbon sources. Physiologically relevant sugars like glucose and fructose are present at low levels in host niches. However, because glucose is the preferred substrate for energy and biosynthesis of structural components, its efficient detection and metabolism are fundamental for the metabolic adaptation of the pathogen. We explored and characterized the C. albicans hexose kinase system composed of one hexokinase ( Ca Hxk2) and two glucokinases ( Ca Glk1 and Ca Glk4). Using a set of mutant strains, we found that hexose phosphorylation is mostly performed by Ca Hxk2, which sustains growth on hexoses. Our data on hexokinase and glucokinase expression point out an absence of cross regulation mechanisms at the transcription level and different regulatory pathways. In the presence of glucose, Ca Hxk2 migrates in the nucleus and contributes to the glucose repression signaling pathway. In addition, Ca Hxk2 participates in oxidative, osmotic and cell wall stress responses, while glucokinases are overexpressed under hypoxia. Hexose phosphorylation is a key step necessary for filamentation that is affected in the hexokinase mutant. Virulence of this mutant is clearly impacted in the Galleria mellonella and macrophage models. Filamentation, glucose phosphorylation and stress response defects of the hexokinase mutant prevent host killing by C. albicans . By contributing to metabolic flexibility, stress response and morphogenesis, hexose kinase enzymes play an essential role in the virulence of C. albicans .

Sugar Phosphorylation Controls Carbon Source Utilization and Virulence of Candida albicans

“…Here, we report that Hxk2 and Glk1/4 are responsible for the conversion of glucose into glucose-6-phosphate, while only Hxk2 converts fructose into fructose-6-phosphate. Furthermore, we show that Hxk1 regulates the expression of HXK2 and GLK1/4, and we demonstrate that Hxk2 affects the glucose transport of C. albicans consistent with a recent report (Laurian et al, 2019). Finally, deletion of kinases or disruption of the glycolytic pathway attenuates the virulence of C. albicans.…”

“…During the course of our work, a paper was published where they analyzed possible enzymes involved in this glucose phosphorylation step. They identified three kinases, Hxk2, Glk1, and Glk4, which were responsible for the phosphorylation of glucose (Laurian et al, 2019). These results are similar to our data, although, based on phylogenetic analysis, we found four ortholog enzymes compared to sugar kinases in S. cerevisiae, Hxk1, Hxk2, Glk1, and Glk4.…”

“…(Sexton et al, 2007;Lagree et al, 2020). In fact, deletion of HXK2 increased the expression of glucose transporter genes HGT7, HGT12, and HXT10 (Laurian et al, 2019). Therefore, we hypothesized that a deletion of HXK2 would increase glucose uptake when compared to the WT, as the hxk2 mutant would result in higher expression of the different glucose transporter genes (Laurian et al, 2019).…”

New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

“…Regarding the therapeutic potential of manipulating fungal metabolism, metabolic adaptation in fungi, especially carbon metabolism, regulates virulence factor expression or recognition by immune cells, and therefore enzymes involved in these pathways could well be used as therapeutic targets . In fact, mutant strains or chemical interventions in glycolysis (Rodaki et al, 2006;Laurian et al, 2019) or fatty acid biosynthesis (Xu et al, 2009) showed defective growth, suggesting that these metabolic pathways can be important targets. Other therapeutic options that target C. albicans metabolism is to trigger endogenous nitric oxide (NO) production using compounds such as mdivi-1, which represses hyphal growth and the yeast-to-hypha transition and promotes metabolic reprogramming in the fungus (Koch et al, 2018).…”

A novel genetic circuitry governing hypoxic metabolic flexibility, commensalism and virulence in the fungal pathogen Candida albicans

“…The transcriptional regulatory network that governs adaptation to hypoxia in C. albicans exhibits a high degree of complexity and interconnectedness between master transcriptional regulators such as the transcription factors Tye7, Gal4 and Ahr1 as well as the Ccr4 mRNA deacetylase [24]. Hypoxia induces a drastic remodelling of the transcriptome of C. albicans and other human fungal pathogens with carbohydrate transcripts including glycolysis, hexose transport, trehalose biosynthesis, fermentation and glycerol metabolism being particularly overrepresented [8,24–30]. We and other have previously shown that the transcription factor Tye7 was required for the reactivation of glycolytic genes when C. albicans experienced hypoxia [14,24,31].…”