<i>Candida albicans</i>transcription factor Rim101 mediates pathogenic interactions through cell wall functions

Nobile, Clarissa J.; Solis, Norma V.; Myers, Carter L.; Fay, Allison; Deneault, Jean-Sebastien; Nantel, André; Mitchell, Aaron P.; Filler, Scott G.

doi:10.1111/j.1462-5822.2008.01198.x

Cited by 142 publications

(146 citation statements)

References 62 publications

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“…Intriguingly, Rim101 activation in other fungal species occurs exclusively through the conserved Rim pathway and not via the cAMP-PKA cascade, unveiling a novel mechanism of Rim101 activation in C. neoformans (436). The hypervirulence phenotype of the rim101 mutant is striking in light of the fact that rim101 mutants exhibit decreased virulence in C. albicans (424) as well as defects in melanization in C. neoformans (339), suggesting that this transcription factor mediates diverse responses upon activation by distinct signaling cascades.…”

Section: Major Morphogenetic Signaling Cascadesmentioning

confidence: 92%

“…The rim8 homozygous deletion mutant has reduced virulence in the mouse model of systemic infection, and the deletion of numerous components of the Rim101 pathway results in attenuated virulence in a mouse model of keratomycosis (135,385,642). Rim101 is required for damage to oral epithelial cells in vitro as well as for virulence in an oropharyngeal candidiasis model of infection (424). As mentioned above, PHR1 and PHR2 are pH-regulated genes and were among the first genes implicated in pH-mediated morphogenesis.…”

Section: Major Morphogenetic Signaling Cascadesmentioning

confidence: 99%

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Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

499

547

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SUMMARY Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans , several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus , which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans , C. neoformans , and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

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Section: Major Morphogenetic Signaling Cascadesmentioning

confidence: 92%

Section: Major Morphogenetic Signaling Cascadesmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

499

547

View full text Add to dashboard Cite

show abstract

“…Epithelial cell damage: C. albicans causes epithelial cell damage, and this damage requires active Rim101 (Villar et al 2007;Nobile et al 2008). We wished to test the ability of our mutant snf7 alleles to mediate epithelial cell damage in a Rim101-dependent and Rim101-independent manner.…”

Section: Resultsmentioning

confidence: 99%

Mutational Analysis of Candida albicans SNF7 Reveals Genetically Separable Rim101 and ESCRT Functions and Demonstrates Divergence in bro1-Domain Protein Interactions

Wolf

Davis²

2010

Genetics

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The opportunistic pathogen Candida albicans can grow over a wide pH range, which is associated with its ability to colonize and infect distinct host niches. C. albicans growth in neutral-alkaline environments requires proteolytic activation of the transcription factor Rim101. Rim101 activation requires Snf7, a member of the endosomal sorting complex required for transport (ESCRT) pathway. We hypothesized that Snf7 has distinct functions in the Rim101 and ESCRT pathways, which we tested by alanine-scanning mutagenesis. While some snf7 alleles conferred no defects, we identified alleles with solely ESCRTdependent, solely Rim101-dependent, or both Rim101-and ESCRT-dependent defects. Thus, Snf7 function in these two pathways is at least partially separable. Both Rim101-and ESCRT-dependent functions require Snf7 recruitment to the endosomal membrane and alleles that disrupted both pathways were found to localize normally, suggesting a downstream defect. Most alleles that conferred solely Rim101-dependent defects were still able to process Rim101 normally under steady-state conditions. However, these same strains did display a kinetic defect in Rim101 processing. Several alleles with solely Rim101-dependent defects mapped to the C-terminal end of Snf7. Further analyses suggested that these mutations disrupted interactions with bro-domain proteins, Rim20 and Bro1, in overlapping but slightly divergent Snf7 domains.

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“…In many other fungi, Rim101 also regulates cell wall processes. For example, C. albicans uses Rim101 to allow for the yeast-hypha transition in response to neutral/alkaline pHs, which is a vital step for tissue invasion and virulence (63,64). Additionally, the C. albicans Rim101 pathway regulates the levels of chitin in the cell (21).…”

Section: Discussionmentioning

confidence: 99%

The Cryptococcus neoformans Rim101 Transcription Factor Directly Regulates Genes Required for Adaptation to the Host

O’Meara

Selvig

et al. 2014

Molecular and Cellular Biology

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cThe Rim101 protein is a conserved pH-responsive transcription factor that mediates important interactions between several fungal pathogens and the infected host. In the human fungal pathogen Cryptococcus neoformans, the Rim101 protein retains conserved functions to allow the microorganism to respond to changes in pH and other host stresses. This coordinated cellular response enables this fungus to effectively evade the host immune response. Preliminary studies suggest that this conserved transcription factor is uniquely regulated in C. neoformans both by the canonical pH-sensing pathway and by the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. Here we present comparative transcriptional data that demonstrate a strong concordance between the downstream effectors of PKA and Rim101. To define Rim101-dependent gene expression during a murine lung infection, we used nanoString profiling of lung tissue infected with a wild-type or rim101⌬ mutant strain. In this setting, we demonstrated that Rim101 controls the expression of multiple cell wall-biosynthetic genes, likely explaining the enhanced immunogenicity of the rim101⌬ mutant. Despite its divergent upstream regulation, the C. neoformans Rim101 protein recognizes a conserved DNA binding motif. Using these data, we identified direct targets of this transcription factor, including genes involved in cell wall regulation. Therefore, the Rim101 protein directly controls cell wall changes required for the adaptation of C. neoformans to its host environment. Moreover, we propose that integration of the cAMP/PKA and pH-sensing pathways allows C. neoformans to respond to a broad range of host-specific signals.

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Candida albicanstranscription factor Rim101 mediates pathogenic interactions through cell wall functions

Cited by 142 publications

References 62 publications

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Mutational Analysis of Candida albicans SNF7 Reveals Genetically Separable Rim101 and ESCRT Functions and Demonstrates Divergence in bro1-Domain Protein Interactions

The Cryptococcus neoformans Rim101 Transcription Factor Directly Regulates Genes Required for Adaptation to the Host

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