Temperature is a critical environmental signal, which exerts powerful control over the development and virulence of diverse microbial pathogens. Fungi, along with other microbial species, exploit a diversity of mechanisms to sense and respond to temperature fluctuations that may be encountered in the host or under other conditions of temperature stress. For Candida albicans, the leading fungal pathogen of humans, temperature influences mating, phenotypic switching, resistance to antifungal drugs, and the morphogenetic transition from yeast to filamentous growth. C. albicans morphogenesis is strongly influenced by temperature, and most filament inducing cues depend on a concurrent increase of temperature to 37˚C before morphogenesis can occur. Further elevated temperature of 39˚C to 42˚C can serve as an independent filament-inducing cue, although the molecular mechanisms underpinning this temperature-dependent morphogenetic transition remain largely uncharacterized. Here, I provide the first comprehensive investigation of the molecular mechanisms mediating temperature-dependent morphogenesis in C. albicans. I establish that the thermally responsive molecular chaperone Hsp90 orchestrates temperature-dependent morphogenesis, and that Hsp90 functions as a key temperature sensor, such that elevated temperature is required to relieve Hsp90-mediated repression of the morphogenetic program. Further, I demonstrate that Hsp90 controls morphogenesis via at least two distinct cellular signaling cascades. First, Hsp90 and its co-chaperone Sgt1 physically interact, and together regulate protein kinase A (PKA) signaling via an interaction with the adenylyl cyclase of the PKA cascade, Cyr1, such that genetic depletion of either Hsp90 or Sgt1 activates PKA signaling and induces filamentation. Second, Hsp90 controls temperature-dependent morphogenesis via previously uncharacterized cellular circuitry comprised of the cyclin-dependent kinase Pho85, the cyclin Pcl1, and the transcriptional regulator Hms1. Together, this research illuminates the central role of Hsp90 in coupling temperature sensing and morphogenesis in the human fungal pathogen C. albicans.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/34918 |
| Date | 07 January 2013 |
| Creators | Shapiro, Rebecca |
| Contributors | Cowen, Leah |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis, Dataset |
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