scholarly journals Comparative Evolution of Morphological Regulatory Functions in Candida Species

2013 ◽  
Vol 12 (10) ◽  
pp. 1356-1368 ◽  
Author(s):  
Erika Lackey ◽  
Geethanjali Vipulanandan ◽  
Delma S. Childers ◽  
David Kadosh
Keyword(s):  
Target Genes ◽  
Pathogenic Fungi ◽  
Specific Gene ◽  
Content Type ◽  
Environmental Signals ◽  
Human Fungal Pathogen ◽  
Evolutionarily Conserved ◽  
Morphological Transitions ◽  
High Level ◽  
Regulatory Functions

ABSTRACTMorphological transitions play an important role in virulence and virulence-related processes in a wide variety of pathogenic fungi, including the most commonly isolated human fungal pathogenCandida albicans. While environmental signals, transcriptional regulators, and target genes associated withC. albicansmorphogenesis are well-characterized, considerably little is known about morphological regulatory mechanisms and the extent to which they are evolutionarily conserved in less pathogenic and less filamentous non-albicans Candidaspecies (NACS). We have identified specific optimal filament-inducing conditions for three NACS (C. tropicalis,C. parapsilosis, andC. guilliermondii), which are very limited, suggesting that these species may be adapted for niche-specific filamentation in the host. Only a subset of evolutionarily conservedC. albicansfilament-specific target genes were induced upon filamentation inC. tropicalis,C. parapsilosis, andC. guilliermondii. One of the genes showing conserved expression wasUME6, a key filament-specific regulator ofC. albicanshyphal development. Constitutive high-level expression ofUME6was sufficient to drive increased filamentation as well as biofilm formation and partly restore conserved filament-specific gene expression in bothC. tropicalisandC. parapsilosis, suggesting that evolutionary differences in filamentation ability among pathogenicCandidaspecies may be partially attributed to alterations in the expression level of a conserved filamentous growth machinery. In contrast toUME6,NRG1, an important repressor ofC. albicansfilamentation, showed only a partly conserved role in controlling NACS filamentation. Overall, our results suggest thatC. albicansmorphological regulatory functions are partially conserved in NACS and have evolved to respond to more specific sets of host environmental cues.

scholarly journals UME6, a Novel Filament-specific Regulator ofCandida albicansHyphal Extension and Virulence

2008 ◽  
Vol 19 (4) ◽  
pp. 1354-1365 ◽  
Author(s):  
Mohua Banerjee ◽  
Delma S. Thompson ◽  
Anna Lazzell ◽  
Patricia L. Carlisle ◽  
Christopher Pierce ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Pathogenic Fungi ◽  
Filamentous Growth ◽  
Specific Gene ◽  
Regulatory Pathways ◽  
Expression Of Genes ◽  
High Level ◽  
Germ Tubes

The specific ability of the major human fungal pathogen Candida albicans, as well as many other pathogenic fungi, to extend initial short filaments (germ tubes) into elongated hyphal filaments is important for a variety of virulence-related processes. However, the molecular mechanisms that control hyphal extension have remained poorly understood for many years. We report the identification of a novel C. albicans transcriptional regulator, UME6, which is induced in response to multiple host environmental cues and is specifically important for hyphal extension. Although capable of forming germ tubes, the ume6Δ/ume6Δ mutant exhibits a clear defect in hyphal extension both in vitro and during infection in vivo and is attenuated for virulence in a mouse model of systemic candidiasis. We also show that UME6 is an important downstream component of both the RFG1-TUP1 and NRG1-TUP1 filamentous growth regulatory pathways, and we provide evidence to suggest that Nrg1 and Ume6 function together by a negative feedback loop to control the level and duration of filament-specific gene expression in response to inducing conditions. Our results suggest that hyphal extension is controlled by a specific transcriptional regulatory mechanism and is correlated with the maintenance of high-level expression of genes in the C. albicans filamentous growth program.

scholarly journals Robust Transcriptional Response to Heat Shock Impacting Diverse Cellular Processes despite Lack of Heat Shock Factor in Microsporidia

mSphere ◽  
2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Nora K. McNamara-Bordewick ◽  
Mia McKinstry ◽  
Jonathan W. Snow
Keyword(s):  
Heat Shock ◽  
Stress Responses ◽  
Target Genes ◽  
Treatment Strategies ◽  
Pathogenic Fungi ◽  
Fungal Species ◽  
Content Type ◽  
Novel Treatment ◽  
Novel Treatment Strategies ◽  
Insight Into

ABSTRACT The majority of fungal species prefer the 12° to 30°C range, and relatively few species tolerate temperatures higher than 35°C. Our understanding of the mechanisms underpinning the ability of some species to grow at higher temperatures is incomplete. Nosema ceranae is an obligate intracellular fungal parasite that infects honey bees and can cause individual mortality and contribute to colony collapse. Despite a reduced genome, this species is strikingly thermotolerant, growing optimally at the colony temperature of 35°C. In characterizing the heat shock response (HSR) in N. ceranae, we found that this and other microsporidian species have lost the transcriptional regulator HSF and possess a reduced set of putative core HSF1-dependent HSR target genes. Despite these losses, N. ceranae demonstrates robust upregulation of the remaining HSR target genes after heat shock. In addition, thermal stress leads to alterations in genes involved in various metabolic pathways, ribosome biogenesis and translation, and DNA repair. These results provide important insight into the stress responses of microsporidia. Such a new understanding will allow new comparisons with other pathogenic fungi and potentially enable the discovery of novel treatment strategies for microsporidian infections affecting food production and human health. IMPORTANCE We do not fully understand why some fungal species are able to grow at temperatures approaching mammalian body temperature. Nosema ceranae, a microsporidium, is a type of fungal parasite that infects honey bees and grows optimally at the colony temperature of 35°C despite possessing cellular machinery for responding to heat stress that is notably simpler than that of other fungi. We find that N. ceranae demonstrates a robust and broad response to heat shock. These results provide important insight into the stress responses of this type of fungus, allow new comparisons with other pathogenic fungi, and potentially enable the discovery of novel treatment strategies for this type of fungus.

scholarly journals Distinct Signaling Pathways from the Circadian Clock Participate in Regulation of Rhythmic Conidiospore Development in Neurospora crassa

2002 ◽  
Vol 1 (2) ◽  
pp. 273-280 ◽  
Author(s):  
Alejandro Correa ◽  
Deborah Bell-Pedersen
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Neurospora Crassa ◽  
Mutant Strain ◽  
Specific Gene ◽  
Developmentally Regulated ◽  
Environmental Signals ◽  
Endogenous Clock ◽  
Environmental Induction ◽  
High Level

ABSTRACT Several different environmental signals can induce asexual spore development (conidiation) and expression of developmentally regulated genes in Neurospora crassa. However, under constant conditions, where no environmental cues for conidiation are present, the endogenous circadian clock in N. crassa promotes daily rhythms in expression of known developmental genes and of conidiation. We anticipated that the same pathway of gene regulation would be followed during clock-controlled conidiation and environmental induction of conidiation and that the circadian clock would need only to control the initial developmental switch. Previous experiments showed that high-level developmental induction of the clock-controlled genes eas (ccg-2) and ccg-1 requires the developmental regulatory proteins FL and ACON-2, respectively, and normal developmental induction of fl mRNA expression requires ACON-2. We demonstrate that the circadian clock regulates rhythmic fl gene expression and that fl rhythmicity requires ACON-2. However, we find that clock regulation of eas (ccg-2) is normal in an fl mutant strain and ccg-1 expression is rhythmic in an acon-2 mutant strain. Together, these data point to the endogenous clock and the environment following separate pathways to regulate conidiation-specific gene expression.

scholarly journals Unisexual Reproduction Enhances Fungal Competitiveness by Promoting Habitat Exploration via Hyphal Growth and Sporulation

2013 ◽  
Vol 12 (8) ◽  
pp. 1155-1159 ◽  
Author(s):  
Sujal S. Phadke ◽  
Marianna Feretzaki ◽  
Joseph Heitman
Keyword(s):  
Mating Type ◽  
Wild Type Strain ◽  
Hyphal Growth ◽  
Pathogenic Fungi ◽  
Selective Advantage ◽  
Sexual Cycle ◽  
Developmental Pathway ◽  
Content Type ◽  
Human Fungal Pathogen ◽  
Unisexual Reproduction

ABSTRACT Unisexual reproduction is a novel homothallic sexual cycle recently discovered in both ascomycetous and basidiomycetous pathogenic fungi. It is a form of selfing that induces the yeast-to-hyphal dimorphic transition in isolates of the α mating type of the human fungal pathogen Cryptococcus neoformans . Unisexual reproduction may benefit the pathogen by facilitating sexual reproduction in the absence of the opposite a mating type and by generating infectious propagules called basidiospores. Here, we report an independent potential selective advantage of unisexual reproduction beyond genetic exchange and recombination. We competed a wild-type strain capable of undergoing unisexual reproduction with mutants defective in this developmental pathway and found that unisexual reproduction provides a considerable dispersal advantage through hyphal growth and sporulation. Our results show that unisexual reproduction may serve to facilitate access to both nutrients and potential mating partners and may provide a means to maintain the capacity for dimorphic transitions in the environment.

scholarly journals The RAM Network in Pathogenic Fungi

2012 ◽  
Vol 11 (6) ◽  
pp. 708-717 ◽  
Author(s):  
Sarah Saputo ◽  
Yeissa Chabrier-Rosello ◽  
Francis C. Luca ◽  
Anuj Kumar ◽  
Damian J. Krysan
Keyword(s):  
Fungal Pathogens ◽  
Pathogenic Fungi ◽  
Fungal Species ◽  
Specific Gene ◽  
Content Type ◽  
Network Function ◽  
Cellular Processes ◽  
Ram Network ◽  
Recent Developments ◽  
Protein Kinase Signaling

ABSTRACT The r egulation of A ce2 and m orphogenesis (RAM) network is a protein kinase signaling pathway conserved among eukaryotes from yeasts to humans. Among fungi, the RAM network has been most extensively studied in the model yeast Saccharomyces cerevisiae and has been shown to regulate a range of cellular processes, including daughter cell-specific gene expression, cell cycle regulation, cell separation, mating, polarized growth, maintenance of cell wall integrity, and stress signaling. Increasing numbers of recent studies on the role of the RAM network in pathogenic fungal species have revealed that this network also plays an important role in the biology and pathogenesis of these organisms. In addition to providing a brief overview of the RAM network in S. cerevisiae , we summarize recent developments in the understanding of RAM network function in the human fungal pathogens Candida albicans , Candida glabrata , Cryptococcus neoformans , Aspergillus fumigatus , and Pneumocystis spp.

scholarly journals N-Acetylglucosamine Induces White-to-Opaque Switching and Mating in Candida tropicalis, Providing New Insights into Adaptation and Fungal Sexual Evolution

2012 ◽  
Vol 11 (6) ◽  
pp. 773-782 ◽  
Author(s):  
Jing Xie ◽  
Han Du ◽  
Guobo Guan ◽  
Yaojun Tong ◽  
Themistoklis K. Kourkoumpetis ◽  
...  
Keyword(s):  
Candida Tropicalis ◽  
Fungal Pathogen ◽  
Intermediate Phase ◽  
Cell Formation ◽  
Pathogenic Fungi ◽  
Opportunistic Pathogen ◽  
Phenotypic Switching ◽  
Content Type ◽  
Human Fungal Pathogen ◽  
Sexual Mating

ABSTRACTPathogenic fungi are capable of switching between different phenotypes, each of which has a different biological advantage. In the most prevalent human fungal pathogen,Candida albicans, phenotypic transitions not only improve its adaptation to a continuously changing host microenvironment but also regulate sexual mating. In this report, we show thatCandida tropicalis, another important human opportunistic pathogen, undergoes reversible and heritable phenotypic switching, referred to as the “white-opaque” transition. Here we show thatN-acetylglucosamine (GlcNAc), an inducer of white-to-opaque switching inC. albicans, promotes opaque-cell formation and mating and also inhibits filamentation in a number of naturalC. tropicalisstrains. Our results suggest that host chemical signals may facilitate this phenotypic switching and mating ofC. tropicalis, which had been previously thought to reproduce asexually. Overexpression of theC. tropicalis WOR1gene inC. albicansinduces opaque-cell formation. Additionally, an intermediate phase between white and opaque was observed inC. tropicalis, indicating that the switching could be tristable.

scholarly journals Multiple Evolutionarily Conserved Domains of Cap2 Are Required for Promoter Recruitment and Iron Homeostasis Gene Regulation

mSphere ◽  
2018 ◽  
Vol 3 (4) ◽  
Author(s):  
Manjit Kumar Srivastav ◽  
Neha Agarwal ◽  
Krishnamurthy Natarajan
Keyword(s):  
Iron Uptake ◽  
Transcriptional Activity ◽  
Iron Homeostasis ◽  
Protein Domains ◽  
Conserved Domains ◽  
Content Type ◽  
Human Fungal Pathogen ◽  
Bzip Domain ◽  
Evolutionarily Conserved ◽  
Promoter Recruitment

ABSTRACTIron is required for growth and metabolism by virtually all organisms. The human fungal pathogenCandida albicanshas evolved multiple strategies to acquire iron. The Cap2/Hap43 transcriptional regulator, essential for robust virulence ofC. albicans, controls iron homeostasis gene expression by promoter binding and repression of iron utilization genes. The expression of iron uptake genes is also dependent on Cap2, although Cap2 was not recruited to its promoters. Cap2, bearing the conserved bipartite HAP4L-bZIP domain, also contains multiple blocks of amino acids that form the highly conserved carboxyl-terminal region. In this study, we sought to identify the requirements of the different domains for Cap2 function. We constructed a series of mutants bearing either point mutations or deletions in the conserved domains and examined Cap2 activity. Deletion of the highly conserved extreme C-terminal region did not impair expression of Cap2 mutant protein but impaired cell growth and expression of iron homeostasis genes under iron-depleted conditions. Mutations in the amino-terminal HAP4L and basic leucine zipper (bZIP) domains also impaired growth and gene expression. Furthermore, chromatin immunoprecipitation (ChIP) assays showed that the HAP4L domain and the bZIP domain are both essential for Cap2 recruitment toACO1andCYC1promoters. Unexpectedly, the C-terminal conserved region was also essential for Cap2 promoter recruitment. Thus, our results suggest that Cap2 employs multiple evolutionarily conserved domains, including the C-terminal domain for its transcriptional activity.IMPORTANCEIron is an essential micronutrient for living cells.Candida albicans, the predominant human fungal pathogen, thrives under diverse environments with vastly different iron levels in the mammalian host. Therefore, to tightly control iron homeostasis,C. albicanshas evolved a set of transcriptional regulators that cooperate to either upregulate or downregulate transcription of iron uptake genes or iron utilization genes. Cap2/Hap43, a critical transcriptional regulator, contains multiple conserved protein domains. In this study, we carried out mutational analyses to identify the functional roles of the conserved protein domains in Cap2. Our results show that the bZIP, HAP4L, and the C-terminal domain are each required for Cap2 transcriptional activity. Thus, Cap2 employs multiple, disparate protein domains for regulation of iron homeostasis inC. albicans.

scholarly journals MrSkn7 Controls Sporulation, Cell Wall Integrity, Autolysis, and Virulence in Metarhizium robertsii

2015 ◽  
Vol 14 (4) ◽  
pp. 396-405 ◽  
Author(s):  
Yanfang Shang ◽  
Peilin Chen ◽  
Yixiong Chen ◽  
Yuzhen Lu ◽  
Chengshu Wang
Keyword(s):  
Cell Wall ◽  
Target Genes ◽  
Response Regulator ◽  
Pathogenic Fungus ◽  
Functional Divergence ◽  
Pathogenic Fungi ◽  
Wild Type ◽  
Metarhizium Robertsii ◽  
Content Type ◽  
Cell Autolysis

ABSTRACT Two-component signaling pathways generally include sensor histidine kinases and response regulators. We identified an ortholog of the response regulator protein Skn7 in the insect-pathogenic fungus Metarhizium robertsii , which we named MrSkn7. Gene deletion assays and functional characterizations indicated that MrSkn7 functions as a transcription factor. The MrSkn7 null mutant of M. robertsii lost the ability to sporulate and had defects in cell wall biosynthesis but was not sensitive to oxidative and osmotic stresses compared to the wild type. However, the mutant was able to produce spores under salt stress. Insect bioassays using these spores showed that the virulence of the mutant was significantly impaired compared to that of the wild type due to the failures to form the infection structure appressorium and evade host immunity. In particular, deletion of MrSkn7 triggered cell autolysis with typical features such as cell vacuolization, downregulation of repressor genes, and upregulation of autolysis-related genes such as extracellular chitinases and proteases. Promoter binding assays confirmed that MrSkn7 could directly or indirectly control different putative target genes. Taken together, the results of this study help us understand the functional divergence of Skn7 orthologs as well as the mechanisms underlying the development and control of virulence in insect-pathogenic fungi.

scholarly journals Evidence for Multiple Mediator Complexes in Yeast Independently Recruited by Activated Heat Shock Factor

2016 ◽  
Vol 36 (14) ◽  
pp. 1943-1960 ◽  
Author(s):  
Jayamani Anandhakumar ◽  
Yara W. Moustafa ◽  
Surabhi Chowdhary ◽  
Amoldeep S. Kainth ◽  
David S. Gross
Keyword(s):  
Heat Shock ◽  
Rna Polymerase Ii ◽  
Target Genes ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Dynamic Complexity ◽  
Content Type ◽  
Evolutionarily Conserved ◽  
Multiple Species

Mediator is an evolutionarily conserved coactivator complex essential for RNA polymerase II transcription. Although it has been generally assumed that inSaccharomyces cerevisiae, Mediator is a stable trimodular complex, its structural statein vivoremains unclear. Using the “anchor away” (AA) technique to conditionally deplete select subunits within Mediator and its reversibly associated Cdk8 kinase module (CKM), we provide evidence that Mediator's tail module is highly dynamic and that a subcomplex consisting of Med2, Med3, and Med15 can be independently recruited to the regulatory regions of heat shock factor 1 (Hsf1)-activated genes. Fluorescence microscopy of a scaffold subunit (Med14)-anchored strain confirmed parallel cytoplasmic sequestration of core subunits located outside the tail triad. In addition, and contrary to current models, we provide evidence that Hsf1 can recruit the CKM independently of core Mediator and that core Mediator has a role in regulating postinitiation events. Collectively, our results suggest that yeast Mediator is not monolithic but potentially has a dynamic complexity heretofore unappreciated. Multiple species, including CKM-Mediator, the 21-subunit core complex, the Med2-Med3-Med15 tail triad, and the four-subunit CKM, can be independently recruited by activated Hsf1 to its target genes in AA strains.

scholarly journals Ppg1, a PP2A-Type Protein Phosphatase, Controls Filament Extension and Virulence in Candida albicans

2014 ◽  
Vol 13 (12) ◽  
pp. 1538-1547 ◽  
Author(s):  
Mohammad T. Albataineh ◽  
Anna Lazzell ◽  
Jose L. Lopez-Ribot ◽  
David Kadosh
Keyword(s):  
Signal Transduction ◽  
Candida Albicans ◽  
Protein Phosphatase ◽  
Target Genes ◽  
Filamentous Growth ◽  
Fine Tuning ◽  
Signal Transduction Pathways ◽  
Content Type ◽  
Human Fungal Pathogen ◽  
Epistasis Analysis

ABSTRACT Candida albicans , a major human fungal pathogen, is the primary cause of invasive candidiasis in a wide array of immunocompromised patients. C. albicans virulence requires the ability to undergo a reversible morphological transition from yeast to filaments in response to a variety of host environmental cues. These cues are sensed by the pathogen and activate multiple signal transduction pathways to induce filamentation. Reversible phosphorylation events are critical for regulation of many of these pathways. While a variety of protein kinases are known to function as components of C. albicans filamentous growth signal transduction pathways, considerably little is known about the role of phosphatases. Here we demonstrate that PPG1 , encoding a putative type 2A-related protein phosphatase, is important for C. albicans filament extension, invasion, and virulence in a mouse model of systemic candidiasis. PPG1 is also important for downregulation of NRG1 , a key transcriptional repressor of C. albicans filamentous growth, and is shown to affect the expression of several filament-specific target genes. An epistasis analysis suggests that PPG1 controls C. albicans filamentation via the cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway. We demonstrate that Ppg1 possesses phosphatase activity and that a ppg1 catalytic mutant shows nearly equivalent filamentation, invasion, and virulence defects compared to those of a ppg1 Δ/Δ strain. Overall, our results suggest that phosphatases, such as Ppg1, play critical roles in controlling and fine-tuning C. albicans filament extension and virulence as well as signal transduction pathways, transcriptional regulators, and target genes associated with these processes.

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