title: Tight control of trehalose content is required for efficient heat-induced cell elongation in Candida albicans.
abstract: The ability to form hyphae in the human pathogenic fungus Candida albicans is a prerequisite for virulence. It contributes to tissue infection, biofilm formation, as well as escape from phagocytes. Cell elongation triggered by human body temperature involves the essential heat shock protein Hsp90, which negatively governs a filamentation program dependent upon the Ras-protein kinase A (PKA) pathway. Tight regulation of Hsp90 function is required to ensure fast appropriate response and maintenance of a wide range of regulatory and signaling proteins. Client protein activation by Hsp90 relies on a conformational change of the chaperone, whose ATPase activity is competitively inhibited by geldanamycin. We demonstrate a novel regulatory mechanism of heat- and Hsp90-dependent induced morphogenesis, whereby the nonreducing disaccharide trehalose acts as a negative regulator of Hsp90 release. By means of a mutant strain deleted for Gpr1, the G protein-coupled receptor upstream of PKA, we demonstrate that elevated trehalose content in that strain, resulting from misregulation of enzymatic activities involved in trehalose metabolism, disrupts the filamentation program in response to heat. Addition of geldanamycin does not result in hyphal extensions at 30 °C in the gpr1Δ/gpr1Δ mutant as it does in wild type cells. In addition, validamycin, a specific inhibitor of trehalase, the trehalose-degrading enzyme, inhibits cell elongation in response to heat and geldanamycin. These results place Gpr1 as a regulator of trehalose metabolism in C. albicans and illustrate that trehalose modulates Hsp90-dependent activation of client proteins and signaling pathways leading to filamentation in the human fungal pathogen.
authors.affiliation: Department of Molecular Microbiology, VIB and Laboratory of Molecular Cell Biology, KU Leuven, Kasteelpark Arenberg 31 bus 2438, 3001 Heverlee, Belgium.
authors.forename: Joke
authors.initials: J
authors.lastname: Serneels
authors.forename: Hélène
authors.initials: H
authors.lastname: Tournu
authors.forename: Patrick
authors.initials: P
authors.lastname: Van Dijck
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002176:Candida albicans / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D019298:Glucose-6-Phosphate / Q000378:metabolism; D005964:Glucosyltransferases / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D025301:Hyphae / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D009024:Morphogenesis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction; D013696:Temperature; D014198:Trehalase / Q000378:metabolism; D014199:Trehalose / Q000378:metabolism*
chemical_list: D005656:Fungal Proteins; D018841:HSP90 Heat-Shock Proteins; D043562:Receptors, G-Protein-Coupled; D019298:Glucose-6-Phosphate; D000255:Adenosine Triphosphate; D014199:Trehalose; D005964:Glucosyltransferases; C023180:trehalose-6-phosphate synthase; D006593:Hexokinase; D017868:Cyclic AMP-Dependent Protein Kinases; D014198:Trehalase