Abstract
Survival of the pathogenic yeast Candida albicans depends upon assimilation of fermentable and non-fermentable carbon sources detected in host microenvironments. Among the various carbon sources encountered in a human body, glucose is the primary source of energy. Its effective detection, metabolism and prioritization via glucose repression are primordial for the metabolic adaptation of the pathogen. In C. albicans, glucose phosphorylation is mainly performed by the hexokinase 2 (CaHxk2). In addition, in the presence of glucose, CaHxK2 migrates in the nucleus and contributes to the glucose repression signaling pathway. Based on the known dual function of the Saccharomyces cerevisiae hexokinase 2 (ScHxk2), we intended to explore the impact of both enzymatic and regulatory functions of CaHxk2 on virulence, using a site-directed mutagenesis approach. We show that the conserved aspartate residue at position 210, implicated in the interaction with glucose, is essential for enzymatic and glucose repression functions but also for filamentation and virulence in macrophages. Point mutations and deletion into the N-terminal region known to specifically affect glucose repression in ScHxk2 proved to be ineffective in CaHxk2. These results clearly show that enzymatic and regulatory functions of the hexokinase 2 cannot be unlinked in C. albicans.
Highlights
For microbial pathogens, the metabolic capacity to assimilate nutrients is a crucial factor to promote infection and commensal colonization
In a previous study [13], we showed that the hexokinase CaHxk2 is essential for fitness and virulence in C. albicans, which was reconfirmed by the work of Wijnants et al [14]
The Regulatory Domains and Catalytic Residues Are Conserved in CaHxk2 In S. cerevisiae, domains implicated in catalytic and regulatory functions were clearly identified [23,27,30,31,35,37,42,43]
Summary
The metabolic capacity to assimilate nutrients is a crucial factor to promote infection and commensal colonization. Candida albicans colonizes diverse host microenvironments (skin, mucosa, blood, organs) [1]. To assimilate the spectrum of alternative carbon sources available and to support C. albicans proliferation in vivo, glyoxylate, lipid β-oxidation and gluconeogenic pathways are essential [2,3,4,5,6,7,8]. Genomic tools revealed the expression of infection-associated genes involved in the glycolytic pathway during the colonization of kidneys and liver and for survival in blood [9,10,11]. During Candida-macrophage interactions, concurrent upregulation of glycolysis occurs in both host and pathogen, leading to glucose competition. By depleting glucose, C. albicans triggers rapid macrophage death [12]
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