Yeast cell wall damage response pathways

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DESCRIPTION (provided by applicant): Candida albicans is the 4th most common nosocomial infective agent in the US alone with a high mortality rate amongst candidemia patients. Signaling pathways control processes critical for adaptation, survival, and pathogenesis. Our broad interest is to understand the roles of signaling pathways in C. albicans survival and pathogenesis. Our objective in this proposal is to determine the signaling mechanism underlying the Psk1-Sko1 cell wall damage response to antifungal drugs. Expression of the transcription factor Sko1 is increased following treatment with the cell wall synthesis inhibitor caspofungin, a recently licensed antifungal drug with a novel target. This increase is dependent on protein kinase Psk1, and culminates with the upregulation of cell wall biosynthesis genes. Our most recent findings show that transcription factor Rlm1 controls Sko1 expression upon cell wall damage. Also, we found that strains containing mutations to the plasma membrane receptor Hgt9 are hypersensitive to caspofungin. Thus, our central hypothesis is that increased SKO1 expression following cell wall damage is caused by Psk1 phosphorylation of transcription factor Rlm1, and activation of this pathway occurs through plasma membrane receptors detecting cell wall perturbation. To test our hypothesis, we propose the following specific aims: 1) To determine the role of transcription factor Rlm1 in the Psk1-Sko1 cell wall damage response; and 2) To determine the upstream signaling components in the Psk1-Sko1 cell wall damage response. This pilot proposal is innovative in the identification of a novel adaptive mechanism to cell wall damage that is unique in C. albicans. Further, it will advance our understanding of the response to a new class of antifungal, which may allow us to anticipate resistance mechanisms and identify synergistic inhibitors. Funding of this pilot proposal will expand research at John Jay College and introduce biomedical research to a student population that currently lacks opportunities in this critical area. PUBLIC HEALTH RELEVANCE: Candida albicans is the major fungal pathogen of humans. C. albicans is the 4th most common nosocomial infective agent in the US alone with a high mortality rate amongst candidemia patients. Signaling pathways are critical for adaptation, survival, and pathogenesis. This proposal is relevant as we will determine the signaling mechanisms that govern the response to antifungal drugs.