Hexokinase 2 Challenges the Moonlight Protein Model.

Survival of the pathogenic yeast 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 glucose phosphorylation is mainly performed by the hexokinase 2 (Hxk2). In addition, in the presence of glucose, HxK2 migrates in the nucleus and contributes to the glucose repression signaling pathway. Based on the known dual function of the hexokinase 2 (Hxk2), we intended to explore the impact of both enzymatic and regulatory functions of Hxk2 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 -terminal region known to specifically affect glucose repression in Hxk2 proved to be ineffective in Hxk2. These results clearly show that enzymatic and regulatory functions of the hexokinase 2 cannot be unlinked in