Transcription Factor Nrg1 Mediates Capsule Formation, Stress Response, and Pathogenesis in<i>Cryptococcus neoformans</i>

Cramer, Kari L.; Gerrald, Quincy D.; Nichols, Connie B.; Price, Michael; Alspaugh, J. Andrew

doi:10.1128/ec.00145-06

Cited by 93 publications

(107 citation statements)

References 55 publications

(50 reference statements)

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“…In contrast to C. albicans, in which the yeast-hyphal morphological transition is essential for pathogenesis, Cryptococcus uses the cAMP-signaling axis to control expression of the polysaccharide capsule, a predominantly virulence-associated phenotype (Alspaugh et al 1997). The hyphal transition during cryptococcal mating is also dependent on cAMP-Nrg1 signaling (Cramer et al 2006), although the detailed signaling mechanisms of this observation have yet to be defined.…”

Section: Environmental Regulation Of Hyphal Morphogenesis Sensing Nutmentioning

confidence: 99%

Fungal Morphogenesis

Lin

Alspaugh

Liu

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Morphogenesis in fungi is often induced by extracellular factors and executed by fungal genetic factors. Cell surface changes and alterations of the microenvironment often accompany morphogenetic changes in fungi. In this review, we will first discuss the general traits of yeast and hyphal morphotypes and how morphogenesis affects development and adaptation by fungi to their native niches, including host niches. Then we will focus on the molecular machinery responsible for the two most fundamental growth forms, yeast and hyphae. Last, we will describe how fungi incorporate exogenous environmental and host signals together with genetic factors to determine their morphotype and how morphogenesis, in turn, shapes the fungal microenvironment. PROPERTIES OF MORPHOGENESIS IN FUNGAL CELLS

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Section: Environmental Regulation Of Hyphal Morphogenesis Sensing Nutmentioning

confidence: 99%

Fungal Morphogenesis

Lin

Alspaugh

Liu

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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“…Both Gat201 and Nrg1 repress some genes involved in cell wall synthesis, but Nrg1 also activates other genes involved in cell wall synthesis, consistent with cell wall remodeling during capsule induction. Nrg1, which is activated by cAMP signaling in Cryptococcus (Cramer et al 2006), also activates PDE2, encoding a phosphodiesterase that reduces cAMP levels (Zaman et al 2008), thus adding a slow, transcriptionally mediated negative feedback loop in cAMP signaling to the fast, post-translational negative feedback loops that have been reported (Hicks et al 2005;Kronstad et al 2011).…”

Section: Chip-experiments Validate Netprophet Predictionsmentioning

confidence: 99%

“…To validate NetProphet in C. neoformans, we focused on Gat201, the only cryptococcal TF for which ChIP data was available (Chun et al 2011); Nrg1, a well-studied capsule regulator (Cramer et al 2006); and Usv101, a capsule regulator described here for the first time. We epitope-tagged the last two and carried out ChIP-seq.…”

Section: Netprophet Predicts Functional Direct Binding Of Tfs To Thementioning

confidence: 99%

Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation

et al. 2015

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Key steps in understanding a biological process include identifying genes that are involved and determining how they are regulated. We developed a novel method for identifying transcription factors (TFs) involved in a specific process and used it to map regulation of the key virulence factor of a deadly fungus-its capsule. The map, built from expression profiles of 41 TF mutants, includes 20 TFs not previously known to regulate virulence attributes. It also reveals a hierarchy comprising executive, midlevel, and "foreman" TFs. When grouped by temporal expression pattern, these TFs explain much of the transcriptional dynamics of capsule induction. Phenotypic analysis of TF deletion mutants revealed complex relationships among virulence factors and virulence in mice. These resources and analyses provide the first integrated, systems-level view of capsule regulation and biosynthesis. Our methods dramatically improve the efficiency with which transcriptional networks can be analyzed, making genomic approaches accessible to laboratories focused on specific physiological processes.[Supplemental material is available for this article.]In this paper we present an efficient means of comprehensively mapping the network of transcription factors (TFs) that regulate a particular physiological process. Our approach cycles through deletion of TFs, expression profiling of TF mutants, model construction, and model-directed selection of TFs for the next round of deletion. This predictive genetics approach identifies TFs that affect the process of interest, providing a valuable complement to undirected mutagenesis and screening. Simultaneously, it builds a network model that explains how the TFs affect the process, yielding novel insights into the biological system under study.Mapping the network that regulates a specific process requires knowing which TFs affect that process. One way to identify such TFs is to screen comprehensive mutant libraries, but generating such libraries is not always feasible. Furthermore, genome-scale screening assays must be fast and scalable; such assays may not exist for the process of interest or may be less sensitive than other, more laborious assays. An alternative approach is to map the targets of all TFs encoded in a genome by using methods such as chromatin-immunoprecipitation (ChIP) or large-scale TF deletion and expression analysis. However, undirected, genome-wide approaches are costly and inefficient for probing a specific biological process in detail. We report a model-guided approach that addresses all of these problems by focusing experimental effort on the TFs most likely to be involved in the process of interest. Furthermore, our approach generates a network that provides mechanistic explanations for the phenotypes of TF deletion mutants.Our approach alternates network building by using an algorithm we call NetProphet with identifying relevant TFs by using an algorithm we call PhenoProphet. NetProphet is a validated method for mapping direct, functional regulation that significantly out...

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“…Recently, it was shown that serotype A pka2 mutants are hypersensitive to osmotic shock under conditions of glucose starvation (353); hypersensitivity to osmotic shock is abolished by the additional disruption of PKA1, suggesting that Pka1 and Pka2 play opposite roles in the osmostress response (353). One of the key transcription factors that functions downstream of Pka1 in C. neoformans is Nrg1 (121). Similar to other components of the cAMP-PKA signaling pathway, nrg1 mutants exhibit reduced pathogenicity in mouse models of infection, and MAT␣ nrg1 mutants form few hyphal structures (121).…”

Section: Major Morphogenetic Signaling Cascadesmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

474

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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Transcription Factor Nrg1 Mediates Capsule Formation, Stress Response, and Pathogenesis inCryptococcus neoformans

Cited by 93 publications

References 55 publications

Fungal Morphogenesis

Fungal Morphogenesis

Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

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