Treating fungal infections is challenging due to the emergence of drug resistance and the limited number of clinically useful antifungal drugs. To improve clinical outcome it will be necessary to develop new antifungal drugs with different mechanisms of action and to discover drugs that improve the fungicidal activity of current antifungals. This study reveals a new role for fungal protein kinase C (PKC) signaling in resistance to drugs targeting the ergosterol biosynthesis pathway in the pathogenic fungus, Candida albicans, and the model yeast, Saccharomyces cerevisiae. PKC signaling enabled survival of antifungal-induced cell membrane stress in part through the mitogen-activated protein kinase (MAPK) cascade and through cross-talk with calcineurin signaling in both species. The molecular chaperone Hsp90, which stabilizes client proteins including calcineurin, also stabilized the terminal C. albicans MAPK, Mkc1. This establishes new circuitry connecting PKC with Hsp90 and calcineurin, and suggests that inhibiting fungal Pkc1 can be a promising strategy for treating life-threatening fungal infections.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/25741 |
| Date | 07 January 2011 |
| Creators | LaFayette, Shantelle |
| Contributors | Cowen, Leah |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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