Interaction of Cryptococcus neoformans Rim101 and protein kinase A regulates capsule

• Published in: PLoS pathogens 2010-02, Vol.6 (2), p.e1000776-e1000776
• Main Authors: O'Meara, Teresa R, Norton, Diana, Price, Michael S, Hay, Christie, Clements, Meredith F, Nichols, Connie B, Alspaugh, J Andrew
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Southern; Blotting, Western; Cell Biology/Cell Signaling; Cell Biology/Gene Expression; Cell Biology/Microbial Growth and Development; Cryptococcus; Cryptococcus neoformans - pathogenicity; Cryptococcus neoformans - physiology; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Defects; Evolutionary Biology/Microbial Evolution and Genomics; Fungal Proteins - genetics; Fungal Proteins - metabolism; Fungi; Gene Expression Regulation, Fungal; Genes, Fungal; Genetic aspects; Genetics and Genomics/Disease Models; Genetics and Genomics/Microbial Evolution and Genomics; Genomics; Host-Parasite Interactions - physiology; Host-parasite relationships; Immunoprecipitation; Infectious Diseases/Fungal Infections; Kinases; Mice; Microorganisms; Microscopy, Fluorescence; Oligonucleotide Array Sequence Analysis; Pathogenesis; Physiological aspects; Proteins; Signal transduction; Signal Transduction - physiology; Studies; Transcription factors; Transcription Factors - metabolism; Virulence
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000776

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.