Abstract
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 rim101Δ mutant strain displays growth defects similar to other fungal species in the presence of alkaline pH, increased salt concentrations, and iron limitation. However, the rim101Δ 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 rim101Δ 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.
Highlights
All cells, including pathogenic microorganisms, must be able to sense and respond to changes in their environment
Our study demonstrates that Rim101 integrates two conserved signal transduction cascades, and it is important in regulating microbial pathogenesis
The C. neoformans genome contains a number of genes involved in the biosynthesis of this capsule, and many of these genes are highly transcriptionally regulated, at least partially in response to the PKA pathway [38]
Summary
All cells, including pathogenic microorganisms, must be able to sense and respond to changes in their environment As these cells enter a human host, they need to protect themselves from the immune system and rapidly adapt to human physiologic conditions, such as low nutrient availability, varying pH, and mammalian concentrations of carbon dioxide [1]. Alterations in pH can affect a large number of cellular processes including membrane and cell wall stability, morphogenesis, protein stability and function, and nutrient uptake [2,3,4,5,6,7,8] Many of these responses to pH are regulated by the Rim101 transcription factor and its homologues (PacC in filamentous fungi). A. nidulans is non-pathogenic, these cellular processes have been associated with virulence in other Aspergillus species
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