Remodeling of Global Transcription Patterns of
            <i>Cryptococcus neoformans</i>
            Genes Mediated by the Stress-Activated HOG Signaling Pathways

Ko, Young-Joon; Yu, Yeong Man; Kim, Gyu Bum; Lee, Gir-Won; Maeng, Pil Jae; Kim, Sang Soo; Floyd, Anna; Heitman, Joseph; Bahn, Yong-Sun

doi:10.1128/ec.00120-09

Cited by 124 publications

(286 citation statements)

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“…SXI1, a gene encoding a homeodomain-containing transcriptional regulator, and GPA2, the G protein ␣ subunit in the MAPK pathway, are highly upregulated in hog1 or ssk1 mutants (277). This implicates elevated GPA2 levels as a mechanism for increased pheromone production and sexual reproduction in these strains.…”

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: 99%

“…75,2011 FUNGAL DRUG RESISTANCE, DEVELOPMENT, AND DISEASE 245 mutants in response to multiple stresses (277). Genes required for antiphagocytic polysaccharide capsule production and melanin biosynthesis were upregulated in these mutants (277).…”

Section: Cryptococcus Neoformans Drug Resistance: the Polyenesmentioning

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

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“…Total RNA was isolated with the RiboEx reagent (GeneAll Biotechnology), as previously described (Ko et al 2009). For control, total RNA prepared from WT and mutant cells was pooled (pooled reference RNA).…”

Section: Total Rna Isolation and Dna Microarray Analysismentioning

confidence: 99%

“…Three independent cultures for each strain were prepared for RNA isolation as biological replicates for DNA microarray analysis. Total RNA was isolated with the RiboEx reagent (GeneAll Biotechnology), as previously described (Ko et al 2009). For control, total RNA prepared from WT and mutant cells was pooled (pooled reference RNA).…”

Section: Total Rna Isolation and Dna Microarray Analysismentioning

confidence: 99%

“…The cDNA was synthesized by using reverse transcriptase (Fermentas) and labeled with Cy5/Cy3 agents (Amersham, Piscataway, NJ), as previously described (Ko et al 2009). For DNA microarray analysis, we used a C. neoformans serotype D 70-mer microarray slide containing 7946 probes (Duke University, Durham, NC).…”

Section: Total Rna Isolation and Dna Microarray Analysismentioning

confidence: 99%

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Rewiring of Signaling Networks Modulating Thermotolerance in the Human Pathogen Cryptococcus neoformans

et al. 2017

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Thermotolerance is a crucial virulence attribute for human pathogens, including the fungus Cryptococcus neoformans that causes fatal meningitis in humans. Loss of the protein kinase Sch9 increases C. neoformans thermotolerance, but its regulatory mechanism has remained unknown. Here, we studied the Sch9-dependent and Sch9-independent signaling networks modulating C. neoformans thermotolerance by using genome-wide transcriptome analysis and reverse genetic approaches. During temperature upshift, genes encoding for molecular chaperones and heat shock proteins were upregulated, whereas those for translation, transcription, and sterol biosynthesis were highly suppressed. In this process, Sch9 regulated basal expression levels or induced/repressed expression levels of some temperature-responsive genes, including heat shock transcription factor (HSF1) and heat shock proteins (HSP104 and SSA1). Notably, we found that the HSF1 transcript abundance decreased but the Hsf1 protein became transiently phosphorylated during temperature upshift. Nevertheless, Hsf1 is essential for growth and its overexpression promoted C. neoformans thermotolerance. Transcriptome analysis using an HSF1 overexpressing strain revealed a dual role of Hsf1 in the oxidative stress response and thermotolerance. Chromatin immunoprecipitation demonstrated that Hsf1 binds to the step-type like heat shock element (HSE) of its target genes more efficiently than to the perfect-or gap-type HSE. This study provides insight into the thermotolerance of C. neoformans by elucidating the regulatory mechanisms of Sch9 and Hsf1 through the genome-scale identification of temperature-dependent genes. KEYWORDS Hsf1; Sch9; transcriptome analysis; high temperature; Cryptococcus neoformans R ESPONSE and adaptation to their host's physiological temperature, 37°, are key virulence attributes for most human fungal pathogens that infect from natural environments at ambient temperature. Cryptococcus neoformans is an example of such a pathogen. This basidiomycetous fungus exists in diverse environment niches and generates infectious yeast cells or spores through bisexual and unisexual differentiation, which are inhaled through the respiratory tract in the host and initially colonize the lungs (Idnurm et al. 2005;Lin and Heitman 2006). C. neoformans is subsequently disseminated into the bloodstream, breaches the central nervous system, and eventually elicits fatal meningoencephalitis, responsible for an estimated hundreds of thousands of deaths annually (Park et al. 2009). During this infectious process, the ability to sense and adapt to temperature upshift are crucial factors for the pathogen to establish the initial colonization of the lungs. Therefore, most mutants that are severely defective in thermotolerance tend to be highly attenuated in virulence. Due to such reasons, signaling cascades governing thermotolerance in fungi have been intensively investigated toward their exploitation as potential antifungal drug targets (Bahn et al. 2007;Bahn and Jung 2013). In...

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