PRR1, a Homolog of Aspergillus nidulans palF, Controls pH-Dependent Gene Expression and Filamentation inCandida albicans

ABSTRACT The pH of the environment has been implicated in controlling the yeast-hypha transition and pathogenesis of Candida albicans. Several C. albicans genes, includingPHR1 and PHR2, are pH dependent in their expression. To investigate the mechanism of pH-dependent expression, we have cloned and characterized PRR1 (for pH response regulator). PRR1 is homologous to palF, a component of the pH response pathway in Aspergillus nidulans. Expression of PRR1 was itself pH dependent, being maximal at acid pH but reduced severalfold at alkaline pH. In aprr1 null mutant the alkaline-induced expression ofPHR1 was completely abolished. Conversely, expression ofPHR2 was no longer repressed at alkaline pH. Aprr1 null mutant exhibited no morphological abnormalities at either pH; however, it lost the ability to form hyphae on medium 199 and on 10% serum plates. The ability to filament on serum was not restored by forced expression of PHR1, indicating that additional PRR1-dependent genes are required for hyphal development. These developmental genes appear to be distinct from those controlled by the developmental regulator EFG1, since theEFG1-dependent gene HWP1 was expressed normally in the prr1 null mutant. We conclude that PRR1encodes a component of the pH-dependent response pathway in C. albicans and that this pathway regulates the expression of multiple components of hyphal development.

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Effect of Environmental pH on Morphological Development of Candida albicans Is Mediated via the PacC-Related Transcription Factor Encoded by PRR2

Journal of Bacteriology ◽

10.1128/jb.181.24.7524-7530.1999 ◽

1999 ◽

Vol 181 (24) ◽

pp. 7524-7530 ◽

Cited By ~ 130

Author(s):

Ana M. Ramon ◽

Amalia Porta ◽

William A. Fonzi

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Candida Albicans ◽

Feedback Loop ◽

Response Regulator ◽

Morphological Development ◽

Alkaline Ph ◽

Ph Response ◽

Related Transcription Factor ◽

Ph Dependent

ABSTRACT The ability to respond to ambient pH is critical to the growth and virulence of the fungal pathogen Candida albicans. This response entails the differential expression of several genes affecting morphogenesis. To investigate the mechanism of pH-dependent gene expression, the C. albicans homolog of pacC, designated PRR2 (for pH response regulator), was identified and cloned. pacC encodes a zinc finger-containing transcription factor that mediates pH-dependent gene expression inAspergillus nidulans. Mutants lacking PRR2 can no longer induce the expression of alkaline-expressed genes or repress acid-expressed genes at alkaline pH. Although the mutation did not affect growth of the cells at acid or alkaline pH, the mutants exhibited medium-conditional defects in filamentation. PRR2was itself expressed in a pH-conditional manner, and its induction at alkaline pH was controlled by PRR1. PRR1 is homologous to palF, a regulator of pacC. Thus,PRR2 expression is controlled by a pH-dependent feedback loop. The results demonstrate that the pH response pathway ofAspergillus is conserved and that this pathway has been adapted to control dimorphism in C. albicans.

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RIM101-Dependent and -Independent Pathways Govern pH Responses in Candida albicans

Molecular and Cellular Biology ◽

10.1128/mcb.20.3.971-978.2000 ◽

2000 ◽

Vol 20 (3) ◽

pp. 971-978 ◽

Cited By ~ 203

Author(s):

Dana Davis ◽

R. Bryce Wilson ◽

Aaron P. Mitchell

Keyword(s):

Gene Expression ◽

Candida Albicans ◽

Cellular Differentiation ◽

Alkaline Ph ◽

Ph Response ◽

Pcr Product ◽

Ph Dependent ◽

Ph Range ◽

The One

ABSTRACT Growth and differentiation of Candida albicans over a broad pH range underlie its ability to infect an array of tissues in susceptible hosts. We identified C. albicans RIM101,RIM20, and RIM8 based on their homology to components of the one known fungal pH response pathway. PCR product-disruption mutations in each gene cause defects in three responses to alkaline pH: filamentation, induction of PRA1and PHR1, and repression of PHR2. We find thatRIM101 itself is an alkaline-induced gene that also depends on Rim20p and Rim8p for induction. Two observations indicate that a novel pH response pathway also exists. First, PHR2 becomes an alkaline-induced gene in the absence of Rim101p, Rim20p, or Rim8p. Second, we created strains in which Rim101p activity is independent of Rim20p and Rim8p; in these strains, filamentation remains pH dependent. Thus, pH governs gene expression and cellular differentiation inC. albicans through both RIM101-dependent andRIM101-independent pathways.

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Modelling the activation of alkaline pH response transcription factor PacC in Aspergillus nidulans: Involvement of a negative feedback loop

Journal of Theoretical Biology ◽

10.1016/j.jtbi.2013.02.006 ◽

2013 ◽

Vol 326 ◽

pp. 11-20 ◽

Cited By ~ 5

Author(s):

Ruian Ke ◽

Ken Haynes ◽

Jaroslav Stark

Keyword(s):

Transcription Factor ◽

Aspergillus Nidulans ◽

Negative Feedback ◽

Feedback Loop ◽

Negative Feedback Loop ◽

Alkaline Ph ◽

Ph Response

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Candida albicansMds3p, a Conserved Regulator of pH Responses and Virulence Identified Through Insertional Mutagenesis

Genetics ◽

10.1093/genetics/162.4.1573 ◽

2002 ◽

Vol 162 (4) ◽

pp. 1573-1581 ◽

Cited By ~ 1

Author(s):

Dana A Davis ◽

Vincent M Bruno ◽

Lucio Loza ◽

Scott G Filler ◽

Aaron P Mitchell

Keyword(s):

Drug Targets ◽

Insertional Mutagenesis ◽

Antibiotic Use ◽

Alkaline Media ◽

Alkaline Ph ◽

Ph Response ◽

New Genes ◽

Ph Dependent ◽

External Ph ◽

Insertion Mutants

AbstractCandida albicans is a commensal fungus that causes diverse infections after antibiotic use or immune debilitation. Gene discovery has been limited because the organism is an asexual diploid. We have developed a strategy that yields random homozygous insertion mutants. The strategy has permitted identification of several prospective essential genes. Many of these genes are homologous to nonessential Saccharomyces cerevisiae genes, and some have no S. cerevisiae homolog. These findings may expand the range of antifungal drug targets. We have also identified new genes required for pH-dependent filamentation, a trait previously associated with virulence. One newly identified gene, MDS3, is required for expression in alkaline media of two filamentation-associated genes, HWP1 and ECE1, but is not required for expression of other pH-response genes. In S. cerevisiae, the two MDS3 homologs are required for growth in alkaline media, thus arguing that Mds3p function in adaptation to external pH changes is conserved. Epistasis tests show that Mds3p contributes to virulence and alkaline pH responses independently of the well-characterized Rim101p pH-response pathway.

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The Transcription Factor Rim101p Governs Ion Tolerance and Cell Differentiation by Direct Repression of the Regulatory Genes NRG1 and SMP1 in Saccharomyces cerevisiae

Molecular and Cellular Biology ◽

10.1128/mcb.23.2.677-686.2003 ◽

2003 ◽

Vol 23 (2) ◽

pp. 677-686 ◽

Cited By ~ 188

Author(s):

Teresa M. Lamb ◽

Aaron P. Mitchell

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcription Factor ◽

Transcriptional Repression ◽

Response Regulator ◽

Alkaline Ph ◽

Ph Response ◽

Induced Genes ◽

Inducible Genes ◽

Direct Activator

ABSTRACT Environmental pH changes have broad consequences for growth and differentiation. The best-understood eukaryotic pH response pathway acts through the zinc-finger transcription factor PacC of Aspergillus nidulans, which activates alkaline pH-induced genes directly. We show here that Saccharomyces cerevisiae Rim101p, the pH response regulator homologous to PacC, functions as a repressor in vivo. Chromatin immunoprecipitation assays show that Rim101p is associated in vivo with the promoters of seven Rim101p-repressed genes. A reporter gene containing deduced Rim101p binding sites is negatively regulated by Rim101p and is associated with Rim101p in vivo. Deletion mutations of the Rim101p repression targets NRG1 and SMP1 suppress rim101Δ mutant defects in ion tolerance, haploid invasive growth, and sporulation. Therefore, transcriptional repression is the main biological function of Rim101p. The Rim101p repression target Nrg1p is in turn required for repression of two alkaline pH-inducible genes, including the Na+ pump gene ENA1, which is required for ion tolerance. Thus, Nrg1p, a known transcriptional repressor, functions as an inhibitor of alkaline pH responses. Our findings stand in contrast to the well-characterized function of PacC as a direct activator of alkaline pH-induced genes yet explain many aspects of Rim101p and PacC function in other organisms.

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The pH-Responsive Regulon of HP0244 (FlgS), the Cytoplasmic Histidine Kinase of Helicobacter pylori

Journal of Bacteriology ◽

10.1128/jb.01219-08 ◽

2008 ◽

Vol 191 (2) ◽

pp. 449-460 ◽

Cited By ~ 30

Author(s):

Yi Wen ◽

Jing Feng ◽

David R. Scott ◽

Elizabeth A Marcus ◽

George Sachs

Keyword(s):

Gene Expression ◽

Helicobacter Pylori ◽

Histidine Kinase ◽

Response Regulator ◽

Transcriptional Profiling ◽

Regulation Of Gene Expression ◽

Mobility Shift ◽

Ph Dependent ◽

Acid Acclimation

ABSTRACT Helicobacter pylori colonizes the acidic gastric environment, in contrast to all other neutralophiles, whose acid resistance and tolerance responses allow only gastric transit. This acid adaptation is dependent on regulation of gene expression in response to pH changes in the periplasm and cytoplasm. The cytoplasmic histidine kinase, HP0244, which until now was thought only to regulate flagellar gene expression via its cognate response regulator, HP0703, was found to generate a response to declining medium pH. Although not required for survival at pH 4.5, HP0244 is required for survival at pH 2.5 with 10 mM urea after 30 min. Transcriptional profiling of a HP0244 deletion mutant grown at pH 7.4 confirmed the contribution of HP0244 to σ54 activation via HP0703 to coordinate flagellar biosynthesis by a pH-independent regulon that includes 14 flagellar genes. Microarray analysis of cells grown at pH 4.5 without urea revealed an additional 22 genes, including 4 acid acclimation genes (ureA, ureB, ureI, and amiE) that are positively regulated by HP0244. Additionally, 86 differentially expressed genes, including 3 acid acclimation genes (ureF, rocF [arginase], and ansB [asparaginase]), were found in cells grown at pH 2.5 with 30 mM urea. Hence, HP0244 has, in addition to the pH-independent flagellar regulon, a pH-dependent regulon, which allows adaptation to a wider range of environmental acid conditions. An acid survival study using an HP0703 mutant and an electrophoretic mobility shift assay with in vitro-phosphorylated HP0703 showed that HP0703 does not contribute to acid survival and does not bind to the promoter regions of several genes in the HP0244 pH-dependent regulon, suggesting that there is a pathway outside the HP0703 regulon which transduces the acid-responsive signal sensed by HP0244.

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Faculty Opinions recommendation of Ehd1, a B-type response regulator in rice, confers short-day promotion of flowering and controls FT-like gene expression independently of Hd1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1019121.218499 ◽

2004 ◽

Author(s):

Detlef Weigel

Keyword(s):

Gene Expression ◽

Response Regulator ◽

Short Day ◽

Type Response

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H2O2 Induces Major Phosphorylation Changes in Critical Regulators of Signal Transduction, Gene Expression, Metabolism and Developmental Networks in Aspergillus nidulans

Journal of Fungi ◽

10.3390/jof7080624 ◽

2021 ◽

Vol 7 (8) ◽

pp. 624

Author(s):

Ulises Carrasco-Navarro ◽

Jesús Aguirre

Keyword(s):

Gene Expression ◽

Protein Phosphorylation ◽

Aspergillus Nidulans ◽

Regulation Of Gene Expression ◽

Antioxidant Response ◽

Eukaryotic Cell ◽

Cell Physiology ◽

Tor Signaling ◽

Developmental Networks ◽

General Metabolism

Reactive oxygen species (ROS) regulate several aspects of cell physiology in filamentous fungi including the antioxidant response and development. However, little is known about the signaling pathways involved in these processes. Here, we report Aspergillus nidulans global phosphoproteome during mycelial growth and show that under these conditions, H2O2 induces major changes in protein phosphorylation. Among the 1964 phosphoproteins we identified, H2O2 induced the phosphorylation of 131 proteins at one or more sites as well as the dephosphorylation of a larger set of proteins. A detailed analysis of these phosphoproteins shows that H2O2 affected the phosphorylation of critical regulatory nodes of phosphoinositide, MAPK, and TOR signaling as well as the phosphorylation of multiple proteins involved in the regulation of gene expression, primary and secondary metabolism, and development. Our results provide a novel and extensive protein phosphorylation landscape in A. nidulans, indicating that H2O2 induces a shift in general metabolism from anabolic to catabolic, and the activation of multiple stress survival pathways. Our results expand the significance of H2O2 in eukaryotic cell signaling.

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Aspergillus nidulans wetA activates spore-specific gene expression.

Molecular and Cellular Biology ◽

10.1128/mcb.11.1.55 ◽

1991 ◽

Vol 11 (1) ◽

pp. 55-62 ◽

Cited By ~ 109

Author(s):

M A Marshall ◽

W E Timberlake

Keyword(s):

Gene Expression ◽

Cell Wall ◽

Aspergillus Nidulans ◽

Gene Activation ◽

Regulatory Function ◽

Specific Gene ◽

Coding Region ◽

Vegetative Cells ◽

Mutant Strains ◽

Late Stages

The Aspergillus nidulans wetA gene is required for synthesis of cell wall layers that make asexual spores (conidia) impermeable. In wetA mutant strains, conidia take up water and autolyze rather than undergoing the final stages of maturation. wetA is activated during conidiogenesis by sequential expression of the brlA and abaA regulatory genes. To determine whether wetA regulates expression of other sporulation-specific genes, its coding region was fused to a nutritionally regulated promoter that permits gene activation in vegetative cells (hyphae) under conditions that suppress conidiation. Expression of wetA in hyphae inhibited growth and caused excessive branching. It did not lead to activation of brlA or abaA but did cause accumulation of transcripts from genes that are normally expressed specifically during the late stages of conidiation and whose mRNAs are stored in mature spores. Thus, wetA directly or indirectly regulates expression of some spore-specific genes. At least one gene (wA), whose mRNA does not occur in spores but rather accumulates in the sporogenous phialide cells, was activated by wetA, suggesting that wetA may have a regulatory function in these cells as well as in spores. We propose that wetA is responsible for activating a set of genes whose products make up the final two conidial wall layers or direct their assembly and through this activity is responsible for acquisition of spore dormancy.

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