Abstract
Pathogenic microorganisms must adapt to changes in their immediate surroundings, including alterations in pH, to survive the shift from the external environment to that of the infected host. In the basidiomycete fungal pathogen Cryptococcus neoformans, these pH changes are primarily sensed by the fungus-specific, alkaline pH-sensing Rim/Pal pathway. The C. neoformans Rim pathway has diverged significantly from that described in ascomycete fungi. We recently identified the C. neoformans putative pH sensor Rra1, which activates the Rim pathway in response to elevated pH. In this study, we probed the function of Rra1 by analyzing its cellular localization and performing protein co-immunoprecipitation to identify potential Rra1 interactors. We found that Rra1 does not strongly colocalize or interact with immediate downstream Rim pathway components. However, these experiments identified a novel Rra1 interactor, the previously uncharacterized C. neoformans nucleosome assembly protein 1 (Nap1), which was required for Rim pathway activation. We observed that Nap1 specifically binds to the C-terminal tail of the Rra1 sensor, probably promoting Rra1 protein stability. This function of Nap1 is conserved in fungi closely related to C. neoformans that contain Rra1 orthologs, but not in the more distantly related ascomycete fungus Saccharomyces cerevisiae In conclusion, our findings have revealed the sophisticated, yet distinct, molecular mechanisms by which closely and distantly related microbial phyla rapidly adapt to environmental signals and changes, such as alterations in pH.
Highlights
Pathogenic microorganisms must adapt to changes in their immediate surroundings, including alterations in pH, to survive the shift from the external environment to that of the infected host
The pHIS3-RRA1-GFP construct was expressed in the rra1⌬ mutant and shown to be functional, effectively rescuing the phenotypic defects demonstrated by the rra1⌬ mutant strain, such as deficient growth on yeast extract-peptone-dextrose (YPD) pH 8 and YPD ϩ 1.5 M NaCl (Fig. S1A)
The nap1⌬ mutant strain displayed no significant difference in expression level of these two genes when compared with the WT. These results suggest that, unlike in C. neoformans, the nucleosome assembly protein 1 (Nap1) protein is not required for Rim pathway activation in S. cerevisiae
Summary
Pathogenic microorganisms must adapt to changes in their immediate surroundings, including alterations in pH, to survive the shift from the external environment to that of the infected host. We found that Rra does not strongly colocalize or interact with immediate downstream Rim pathway components These experiments identified a novel Rra interactor, the previously uncharacterized C. neoformans nucleosome assembly protein 1 (Nap1), which was required for Rim pathway activation. We observed that Nap binds to the C-terminal tail of the Rra sensor, probably promoting Rra protein stability This function of Nap is conserved in fungi closely related to C. neoformans that contain Rra orthologs, but not in the more distantly related ascomycete fungus Saccharomyces cerevisiae. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The pathogen must respond to these many stressful conditions to survive in the host
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