The pathogenic fungus Cryptococcus neoformans has emerged as the primary cause of community acquired meningitis in regions of the world plagued by HIV infection. Our previous studies have demonstrated a role for post-transcriptional gene regulation in stress tolerance. Our long term goal is to systematically map the protein-RNA interactions that C. neoformans requires for the maintenance of stress tolerance and pathogenicity. We hypothesize that these RNA-protein interactions contribute to the adaptability of C. neoformans, conferring agility to gene expression independent of the nucleus. In this proposal, our focus is two-pronged: First we will identify the RNA binding protein that is interacting with a GGAUG cis element in ribosomal protein transcripts found up-regulated in the ccr4? mutant, and determine its role in stress tolerance and pathogenicity. Second, we will determine the role of the C. neoformans PUF family of RNA binding proteins in stress tolerance and pathogenicity. For both the GGAUG-binding protein and the PUF proteins, we will determine the complement of transcripts that interact with each, allowing us to assemble their respective RNA regulons. Future studies will then build on this work and expand to additional classes or RNA binding proteins. Ultimately, the identification of RNA-protein interactions important for C. neoformans stress tolerance and pathogenicity will provide us with specific targets for novel small-molecule based therapeutics.

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The long term goal of this project is to determine the RNA-protein interactions which C. neoformans requires for stress adaptation and pathogenesis. These studies will enhance our understanding of the molecular reprogramming that accompanies stress adaptation important pathogen. In defining these important RNA- protein interactions, we will determine those that will be viable targets for small-molecule therapeutics.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Duncan, Rory A
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State University of New York at Buffalo
Schools of Medicine
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Banerjee, Dithi; Bloom, Amanda L M; Panepinto, John C (2016) Opposing PKA and Hog1 signals control the post-transcriptional response to glucose availability in Cryptococcus neoformans. Mol Microbiol 102:306-320
Kaur, Jan Naseer; Panepinto, John C (2016) Morphotype-specific effector functions of Cryptococcus neoformans PUM1. Sci Rep 6:23638
Glazier, Virginia E; Kaur, Jan Naseer; Brown, Nancy T et al. (2015) Puf4 regulates both splicing and decay of HXL1 mRNA encoding the unfolded protein response transcription factor in Cryptococcus neoformans. Eukaryot Cell 14:385-95
Bloom, Amanda L M; Panepinto, John C (2014) RNA biology and the adaptation of Cryptococcus neoformans to host temperature and stress. Wiley Interdiscip Rev RNA 5:393-406
Glazier, Virginia E; Panepinto, John C (2014) The ER stress response and host temperature adaptation in the human fungal pathogen Cryptococcus neoformans. Virulence 5:351-6
Banerjee, Dithi; Burkard, Lauren; Panepinto, John C (2014) Inhibition of nucleotide biosynthesis potentiates the antifungal activity of amphotericin B. PLoS One 9:e87246
Panepinto, John C; Heinz, Eva; Traven, Ana (2013) The cellular roles of Ccr4-NOT in model and pathogenic fungi-implications for fungal virulence. Front Genet 4:302
Bloom, Amanda L M; Solomons, J T Graham; Havel, Virginia E et al. (2013) Uncoupling of mRNA synthesis and degradation impairs adaptation to host temperature in Cryptococcus neoformans. Mol Microbiol 89:65-83