Transcriptional Regulation of Carbohydrate Metabolism in the Human Pathogen Candida albicans

Abstract

Glycolysis is a metabolic pathway that is central to the assimilation of carbon for either respiration or fermentation and therefore is critical for the growth of all organisms. Consequently, glycolytic transcriptional regulation is important for the metabolic flexibility of pathogens in their attempts to colonize diverse niches. We investigated the transcriptional control of carbohydrate metabolism in the human fungal pathogen Candida albicans and identified two factors, Tye7p and Gal4p, as key regulators of glycolysis. When respiration was inhibited or oxygen was limited, a gal4tye7 C. albicans strain showed a severe growth defect when cultured on glucose, fructose or mannose as carbon sources. The gal4tye7 strain displayed attenuated virulence in both Galleria and mouse models as well, supporting the connection between pathogenicity and metabolism. Chromatin immunoprecipitation coupled with microarray analysis (ChIP-CHIP) and transcription profiling revealed that Tye7p bound the promoter sequences of the glycolytic genes and activated their expression during growth on either fermentable or non-fermentable carbon sources. Gal4p also bound the glycolytic promoter sequences and activated the genes although to a lesser extent than Tye7p. Intriguingly, binding and activation by Gal4p was carbon source-dependent and much stronger during growth on media containing fermentable sugars than on glycerol. Furthermore, Tye7p and Gal4p were responsible for the complete induction of the glycolytic genes under hypoxic growth conditions. Tye7p and Gal4p also regulated unique sets of carbohydrate metabolic genes; Tye7p bound and activated genes involved in trehalose, glycogen, and glycerol metabolism, while Gal4p regulated the pyruvate dehydrogenase complex. This suggests that Tye7p represents the key transcriptional regulator of carbohydrate metabolism in C. albicans and Gal4p provides a carbon source-dependent fine-tuning of gene expression while regulating the metabolic flux between respiration and fermentation pathways.

E4F1 controls a transcriptional program essential for pyruvate dehydrogenase activity

“…Thus, in E. coli, the aceE/E1, the aceF/E2, and IpdA/E3 genes form a single operon that also includes the transcriptional regulator of this operon PdpR (7). In C. albicans, the Gal4p transcriptional regulator controls the expression of the five main components of the PDC complex, including the Pda1/E1, Pdb1/E1, Dlat1/E2, Lpd1/E3, and Pdx1 subunits (8). Our data reveal that such a coordinated transcriptional program, important for PDH-mediated pyruvate oxidation, also exists in mammals.…”

“…So far, finetuning of PDC activity has been mainly attributed to posttranslational modifications of its subunits (5,6), including the extensively studied phosphorylation of PDHA1/E1 modulated by PDH kinases (PDK1-4) and phosphatases (PDP1-2). However, in lower organisms, such as Escherichia coli and Candida albicans, PDC is also controlled at the transcriptional level by the coordinated regulation of genes encoding its components and regulators (7,8). The importance of such transcriptional regulation of the PDC in mammals remains elusive.…”

Interspecies competition triggers virulence and mutability in Candida albicans–Pseudomonas aeruginosa mixed biofilms

“…We observed that, in mixed biofilms, C. albicans overexpressed hexokinase isoenzyme 2, Hxk2p, which has been demonstrated to be induced in the presence of glucose (Askew et al, 2009). In contrast, other proteins involved in glycolysis/gluconeogenesis (Tdh3p and Pgk1p) and pyruvate metabolism (Pdc11p, Pda1p and Lpd1p) were downregulated, suggesting that glucose metabolism was altered by the interaction with P. aeruginosa (Figure 8).…”

Rearrangements of the transcriptional regulatory networks of metabolic pathways in fungi

“…In addition to the Gal4 protein linked to the glycolytic circuit, recent evidence suggests that the C. albicans ortholog of the bHLH transcription factor Tye7 is a key regulator of the transcriptional control of carbohydrate metabolism in the pathogen. ChIP-CHIP analysis shows that both Tye7 and Gal4 bind upstream the glycolytic pathway genes, and loss of these two factors prevents C. albicans growth under anaerobic conditions and when the cells are forced to grow fermentatively due to decoupling of oxidative phosphorylation [61]. Because Tye7 is a minor element in the regulation of glycolytic genes in S. cerevisiae and Gal4 is limited to the regulation of the Leloir pathway genes required for galactose catabolism, the yeast and C. albicans regulatory circuits have significantly diverged.…”