Interaction of Cryptococcus neoformans Rim101 and protein kinase A regulates capsule.
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Cryptococcus neoformans is a prevalent human fungal pathogen that must survive within various tissues in order to establish a human infection. We have identified the C. neoformans Rim101 transcription factor, a highly conserved pH-response regulator in many fungal species. The rim101 multiply sign in circle mutant strain displays growth defects similar to other fungal species in the presence of alkaline pH, increased salt concentrations, and iron limitation. However, the rim101 multiply sign in circle strain is also characterized by a striking defect in capsule, an important virulence-associated phenotype. This capsular defect is likely due to alterations in polysaccharide attachment to the cell surface, not in polysaccharide biosynthesis. In contrast to many other C. neoformans capsule-defective strains, the rim101 multiply sign in circle mutant is hypervirulent in animal models of cryptococcosis. Whereas Rim101 activation in other fungal species occurs through the conserved Rim pathway, we demonstrate that C. neoformans Rim101 is also activated by the cAMP/PKA pathway. We report here that C. neoformans uses PKA and the Rim pathway to regulate the localization, activation, and processing of the Rim101 transcription factor. We also demonstrate specific host-relevant activating conditions for Rim101 cleavage, showing that C. neoformans has co-opted conserved signaling pathways to respond to the specific niche within the infected host. These results establish a novel mechanism for Rim101 activation and the integration of two conserved signaling cascades in response to host environmental conditions.
Cyclic AMP-Dependent Protein Kinases
Gene Expression Regulation, Fungal
Oligonucleotide Array Sequence Analysis
Published Version (Please cite this version)10.1371/journal.ppat.1000776
Publication InfoO'Meara, Teresa R; Norton, Diana; Price, Michael S; Hay, Christie; Clements, Meredith F; Nichols, Connie B; & Alspaugh, J Andrew (2010). Interaction of Cryptococcus neoformans Rim101 and protein kinase A regulates capsule. PLoS Pathog, 6(2). pp. e1000776. 10.1371/journal.ppat.1000776. Retrieved from https://hdl.handle.net/10161/4592.
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Professor of Medicine
The focus of my research is to understand the ways in which microorganisms sense and respond to changes in their environment. As microbial pathogens enter the infected host, dramatic genetic and phenotypic events occur that allow these organisms to survive in this harsh environment. We study the model fungal organism Cryptococcus neoformans to define signal transduction pathways associated with systemic fungal diseases. This pathogenic fungus causes lethal infections of the ce