PMID:20174553

Citation	O'Meara, TR, Norton, D, Price, MS, Hay, C, Clements, MF, Nichols, CB and Alspaugh, JA (2010) Interaction of Cryptococcus neoformans Rim101 and protein kinase A regulates capsule. PLoS Pathog. 6:e1000776
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 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.
Links	PubMed PMC2824755 Online version:10.1371/journal.ppat.1000776
Keywords	Animals; Blotting, Southern; Blotting, Western; Cryptococcus neoformans/pathogenicity; Cryptococcus neoformans/physiology; Cyclic AMP-Dependent Protein Kinases/genetics; Cyclic AMP-Dependent Protein Kinases/metabolism; Fungal Proteins/genetics; Fungal Proteins/metabolism; Gene Expression Regulation, Fungal; Genes, Fungal; Host-Parasite Interactions/physiology; Immunoprecipitation; Mice; Microscopy, Fluorescence; Oligonucleotide Array Sequence Analysis; Signal Transduction/physiology; Transcription Factors/metabolism; Virulence
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
CRYNJ:PACC	involved_in	GO:0006351: transcription, DNA-templated	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
CRYNJ:PACC	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
CRYNJ:PACC		GO:0006351: transcription, DNA-dependent	ECO:0000315:		P		Figure 1A, 1B, Table 2.	complete CACAO 2307
CRYNJ:PACC		GO:0005634: nucleus	ECO:0000314:		C		Figure 3	complete CACAO 2308
CRYNE:Q9HFW0	involved_in	GO:0042306: regulation of protein import into nucleus	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
CRYNE:Q9HFW0		GO:0042306: regulation of protein import into nucleus	ECO:0000315:		P		Figure 3. Rim101 localization is dependent on PKA	complete CACAO 2309
CRYNJ:PALA	involved_in	GO:0042306: regulation of protein import into nucleus	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
CRYNJ:PALA		GO:0042306: regulation of protein import into nucleus	ECO:0000315:		P		Figure 3. Rim101 localization in the nucleus is dependent on Rim20	complete CACAO 2310

References

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