The Hsp70 member, Ssa1, acts as a DNA‐binding transcriptional co‐activator of laccase in <i>Cryptococcus neoformans</i>

Zhang, Shirong; Hacham, Moshe; Panepinto, John C.; Hu, Guowu; Shin, Soowan; Zhu, Xudong; Williamson, Peter R.

doi:10.1111/j.1365-2958.2006.05422.x

Cited by 60 publications

(48 citation statements)

References 37 publications

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“…These are the first reporter assays of their kind conducted in C. neoformans, as all other transcriptional reporter assays in this system have utilized large, intact promoter sequences of interest rather than inserting small regulatory sequences into an alternate promoter context (Mare et al 2005;Zhang et al 2006;Tommasino et al 2008). By introducing PRE sequences to the URA5 promoter, we were able to confer Mat2-dependent pheromone responsiveness to this normally nonresponsive promoter.…”

Section: Discussionmentioning

confidence: 95%

“…Although the C. neoformans system is highly amenable to many molecular genetic techniques, the use of transcriptional reporter constructs has been limited (Zhang et al 1999(Zhang et al , 2006Mare et al 2005;Tommasino et al 2008). As a consequence, there is no generally established reporter system in which to assay cis-regulatory element function.…”

Section: Discussionmentioning

confidence: 99%

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Analysis ofCryptococcus neoformansSexual Development Reveals Rewiring of the Pheromone-Response Network by a Change in Transcription Factor Identity

Kruzel¹,

Giles²,

Hull

2012

Genetics

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The fundamental mechanisms that control eukaryotic development include extensive regulation at the level of transcription. Gene regulatory networks, composed of transcription factors, their binding sites in DNA, and their target genes, are responsible for executing transcriptional programs. While divergence of these control networks drives species-specific gene expression that contributes to biological diversity, little is known about the mechanisms by which these networks evolve. To investigate how network evolution has occurred in fungi, we used a combination of microarray expression profiling, cis-element identification, and transcription-factor characterization during sexual development of the human fungal pathogen Cryptococcus neoformans. We first defined the major gene expression changes that occur over time throughout sexual development. Through subsequent bioinformatic and molecular genetic analyses, we identified and functionally characterized the C. neoformans pheromone-response element (PRE). We then discovered that transcriptional activation via the PRE requires direct binding of the high-mobility transcription factor Mat2, which we conclude functions as the elusive C. neoformans pheromone-response factor. This function of Mat2 distinguishes the mechanism of regulation through the PRE of C. neoformans from all other fungal systems studied to date and reveals species-specific adaptations of a fungal transcription factor that defies predictions on the basis of sequence alone. Overall, our findings reveal that pheromone-response network rewiring has occurred at the level of transcription factor identity, despite the strong conservation of upstream and downstream components, and serve as a model for how selection pressures act differently on signaling vs. gene regulatory components during eukaryotic evolution.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Analysis ofCryptococcus neoformansSexual Development Reveals Rewiring of the Pheromone-Response Network by a Change in Transcription Factor Identity

Kruzel¹,

Giles²,

Hull

2012

Genetics

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“…Adler et al (2011) first characterized CNAG_01727 (named Ssa1), which is orthologous to an Hsp70 member protein, Ssa1, in S. cerevisiae. Intriguingly, Ssa1 is a DNA-binding transcriptional coactivator of laccase in C. neoformans (Zhang et al 2006). CNAG_01750 also encodes an Ssa1-like protein in C. neoformans, named SSA2.…”

Section: Hsf1 Promotes C Neoformans Thermotolerancementioning

confidence: 99%

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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“…Coimmunoprecipitation was performed by an adaptation of the method of Zhang et al (60). Briefly, rabbit anti-Atg6…”

Section: Antibody Staining Western Blotting and Coimmunoprecipitationmentioning

confidence: 99%

PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans

Hu¹,

Hacham²,

Waterman³

et al. 2008

J. Clin. Invest.

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167

126

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Autophagy is a process by which cells recycle cytoplasm and defective organelles during stress situations such as nutrient starvation. It can also be used by host cells as an immune defense mechanism to eliminate infectious pathogens. Here we describe the use of autophagy as a survival mechanism and virulence-associated trait by the human fungal pathogen Cryptococcus neoformans. We report that a mutant form of C. neoformans lacking the Vps34 PI3K (vps34Δ), which is known to be involved in autophagy in ascomycete yeast, was defective in the formation of autophagy-related 8-labeled (Atg8-labeled) vesicles and showed a dramatic attenuation in virulence in mouse models of infection. In addition, autophagic vesicles were observed in WT but not vps34Δ cells after phagocytosis by a murine macrophage cell line, and Atg8 expression was exhibited in WT C. neoformans during human infection of brain. To dissect the contribution of defective autophagy in vps34Δ C. neoformans during pathogenesis, a strain of C. neoformans in which Atg8 expression was knocked down by RNA interference was constructed and these fungi also demonstrated markedly attenuated virulence in a mouse model of infection. These results demonstrated PI3K signaling and autophagy as a virulence-associated trait and survival mechanism during infection with a fungal pathogen. Moreover, the data show that molecular dissection of such pathogen stress-response pathways may identify new approaches for chemotherapeutic interventions.

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The Hsp70 member, Ssa1, acts as a DNA‐binding transcriptional co‐activator of laccase in Cryptococcus neoformans

Cited by 60 publications

References 37 publications

Analysis ofCryptococcus neoformansSexual Development Reveals Rewiring of the Pheromone-Response Network by a Change in Transcription Factor Identity

Analysis ofCryptococcus neoformansSexual Development Reveals Rewiring of the Pheromone-Response Network by a Change in Transcription Factor Identity

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

PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans

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