title: Cdc28 provides a molecular link between Hsp90, morphogenesis, and cell cycle progression in Candida albicans.
abstract: The trimorphic fungus Candida albicans is the leading cause of systemic candidiasis, a disease with poor prognosis affecting immunocompromised individuals. The capacity of C. albicans to transition between morphological states is a key determinant of its ability to cause life-threatening infection. Recently the molecular chaperone heat shock protein 90 (Hsp90) was implicated as a major regulator of temperature-dependent C. albicans morphogenesis; compromising Hsp90 function induces filamentation and relieves repression of Ras1-protein kinase A (PKA) signaling, although the mechanism involved remains unknown. Here we demonstrate that filaments generated by compromise of Hsp90 function are neither pseudohyphae nor hyphae but closely resemble filaments formed in response to cell cycle arrest. Closer examination revealed that these filaments exhibit a delay in mitotic exit mediated by the checkpoint protein Bub2. Furthermore, Hsp90 inhibition also led to a distinct morphology with defects in cytokinesis. We found that the cyclin-dependent kinase Cdc28 was destabilized in response to depletion of Hsp90 and that Cdc28 physically interacts with Hsp90, implicating this major cell cycle regulator as a novel Hsp90 client protein in C. albicans. Taken together, our results suggest that Hsp90 is instrumental in the regulation of cell division during yeast-form growth in C. albicans and exerts its major effects during late cell cycle events.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: Senn
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Shapiro
authors.forename: Leah E
authors.initials: LE
authors.lastname: Cowen
mesh_terms: D042846:CDC2-CDC28 Kinases / Q000378:metabolism*; D002176:Candida albicans / Q000166:cytology* / Q000254:growth & development* / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025301:Hyphae / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D008938:Mitosis
chemical_list: D018841:HSP90 Heat-Shock Proteins; D042846:CDC2-CDC28 Kinases
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