scholarly journals Rsr1 Focuses Cdc42 Activity at Hyphal Tips and Promotes Maintenance of Hyphal Development in Candida albicans

2012 ◽  
Vol 12 (4) ◽  
pp. 482-495 ◽  
Author(s):  
Rebecca Pulver ◽  
Timothy Heisel ◽  
Sara Gonia ◽  
Robert Robins ◽  
Jennifer Norton ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Rho Gtpase ◽  
Model Organism ◽  
Polarized Growth ◽  
Nucleotide Exchange ◽  
Transcriptional Program ◽  
Content Type ◽  
Hyphal Morphogenesis ◽  
Cell Shapes ◽  
Multiple Cell

ABSTRACTThe extremely elongated morphology of fungal hyphae is dependent on the cell's ability to assemble and maintain polarized growth machinery over multiple cell cycles. The different morphologies of the fungusCandida albicansmake it an excellent model organism in which to study the spatiotemporal requirements for constitutive polarized growth and the generation of different cell shapes. InC. albicans, deletion of the landmark protein Rsr1 causes defects in morphogenesis that are not predicted from study of the orthologous protein in the related yeastSaccharomyces cerevisiae, thus suggesting that Rsr1 has expanded functions during polarized growth inC. albicans. Here, we show that Rsr1 activity localizes to hyphal tips by the differential localization of the Rsr1 GTPase-activating protein (GAP), Bud2, and guanine nucleotide exchange factor (GEF), Bud5. In addition, we find that Rsr1 is needed to maintain the focused localization of hyphal polarity structures and proteins, including Bem1, a marker of the active GTP-bound form of the Rho GTPase, Cdc42. Further, our results indicate that tip-localized Cdc42 clusters are associated with the cell's ability to express a hyphal transcriptional program and that the ability to generate a focused Cdc42 cluster in early hyphae (germ tubes) is needed to maintain hyphal morphogenesis over time. We propose that inC. albicans, Rsr1 “fine-tunes” the distribution of Cdc42 activity and that self-organizing (Rsr1-independent) mechanisms of polarized growth are not sufficient to generate narrow cell shapes or to provide feedback to the transcriptional program during hyphal morphogenesis.

scholarly journals The Ndr/LATS Kinase Cbk1 Regulates a Specific Subset of Ace2 Functions and Suppresses the Hypha-to-Yeast Transition in Candida albicans

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Rohan S. Wakade ◽  
Laura C. Ristow ◽  
Mark A. Stamnes ◽  
Anuj Kumar ◽  
Damian J. Krysan
Keyword(s):  
Candida Albicans ◽  
Regulatory Network ◽  
Transcriptional Analysis ◽  
Large Set ◽  
Phase Growth ◽  
Content Type ◽  
Hyphal Morphogenesis ◽  
Specific Subset ◽  
Wide Range ◽  
Yeast Phase

ABSTRACT The regulation of Ace2 and morphogenesis (RAM) pathway is an important regulatory network in the human fungal pathogen Candida albicans. The RAM pathway’s two most well-studied components, the NDR/Lats kinase Cbk1 and its putative substrate, the transcription factor Ace2, have a wide range of phenotypes and functions. It is not clear, however, which of these functions are specifically due to the phosphorylation of Ace2 by Cbk1. To address this question, we first compared the transcriptional profiles of CBK1 and ACE2 deletion mutants. This analysis indicates that, of the large number of genes whose expression is affected by deletion of CBK1 and ACE2, only 5.5% of those genes are concordantly regulated. Our data also suggest that Ace2 directly or indirectly represses a large set of genes during hyphal morphogenesis. Second, we generated strains containing ACE2 alleles with alanine mutations at the Cbk1 phosphorylation sites. Phenotypic and transcriptional analysis of these ace2 mutants indicates that, as in Saccharomyces cerevisiae, Cbk1 regulation is important for daughter cell localization of Ace2 and cell separation during yeast-phase growth. In contrast, Cbk1 phosphorylation of Ace2 plays a minor role in C. albicans yeast-to-hypha transition. We have, however, discovered a new function for the Cbk1-Ace2 axis. Specifically, Cbk1 phosphorylation of Ace2 prevents the hypha-to-yeast transition. To our knowledge, this is one of the first regulators of the C. albicans hypha-to-yeast transition to be described. Finally, we present an integrated model for the role of Cbk1 in the regulation of hyphal morphogenesis in C. albicans. IMPORTANCE The regulation of Ace2 and morphogenesis (RAM) pathway is a key regulatory network that plays a role in many aspects of C. albicans pathobiology. In addition to characterizing the transcriptional effects of this pathway, we discovered that Cbk1 and Ace2, a key RAM pathway regulator-effector pair, mediate a specific set of the overall functions of the RAM pathway. We have also discovered a new function for the Cbk1-Ace2 axis: suppression of the hypha-to-yeast transition. Very few regulators of this transition have been described, and our data indicate that maintenance of hyphal morphogenesis requires suppression of yeast phase growth by Cbk1-regulated Ace2.

scholarly journals Sch9 Kinase Integrates Hypoxia and CO2Sensing To Suppress Hyphal Morphogenesis in Candida albicans

2011 ◽  
Vol 10 (4) ◽  
pp. 502-511 ◽  
Author(s):  
Catrin Stichternoth ◽  
Alida Fraund ◽  
Eleonora Setiadi ◽  
Luc Giasson ◽  
Anna Vecchiarelli ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Wild Type Strain ◽  
Cell Wall Proteins ◽  
Content Type ◽  
Chronological Aging ◽  
Hyphal Morphogenesis ◽  
Hypha Formation ◽  
Virulence Trait ◽  
Genes Encoding ◽  
A Minor

ABSTRACTThe yeast-hypha transition is an important virulence trait ofCandida albicans. We report that the AGC kinase Sch9 prevents hypha formation specifically under hypoxia at high CO2levels.sch9mutants showed no major defects in growth and stress resistance but a striking hyperfilamentous phenotype under hypoxia (<10% O2), although only in the presence of elevated CO2levels (>1%) and at temperatures of <37°C during surface growth. Thesch9hyperfilamentous phenotype was independent of Rim15 kinase and was recreated by inhibition of Tor1 kinase by rapamycin or caffeine in a wild-type strain, suggesting that Sch9 suppression requires Tor1. Caffeine inhibition also revealed that both protein kinase A isoforms, as well as transcription factors Czf1 and Ace2, are required to generate thesch9mutant phenotype. Transcriptomal analyses showed that Sch9 regulates most genes solely under hypoxia and in the presence of elevated CO2. In this environment, Sch9 downregulates genes encoding cell wall proteins and nutrient transporters, while under normoxia Sch9 and Tor1 coregulate a minor fraction of Sch9-regulated genes, e.g., by inducing glycolytic genes. Other than inSaccharomyces cerevisiae, bothsch9andrim15mutants showed decreased chronological aging under normoxia but not under hypoxia, indicating significant rewiring of the Tor1-Sch9-Rim15 pathway inC. albicans. The results stress the importance of environmental conditions on Sch9 function and establish a novel response circuitry to both hypoxia and CO2inC. albicans, which suppresses hypha formation but also allows efficient nutrient uptake, metabolism, and virulence.

scholarly journals SR-Like RNA-Binding Protein Slr1 Affects Candida albicans Filamentation and Virulence

2013 ◽  
Vol 81 (4) ◽  
pp. 1267-1276 ◽  
Author(s):  
Chaiyaboot Ariyachet ◽  
Norma V. Solis ◽  
Yaoping Liu ◽  
Nemani V. Prasadarao ◽  
Scott G. Filler ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Candida Albicans ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Umbilical Vein ◽  
Polarized Growth ◽  
Content Type ◽  
Fungal Burden

ABSTRACTCandida albicanscauses both mucosal and disseminated infections, and its capacity to grow as both yeast and hyphae is a key virulence factor. Hyphal formation is a type of polarized growth, and members of the SR (serine-arginine) family of RNA-binding proteins influence polarized growth of bothSaccharomyces cerevisiaeandAspergillus nidulans. Therefore, we investigated whether SR-like proteins affect filamentous growth and virulence ofC. albicans. BLAST searches withS. cerevisiaeSR-like protein Npl3 (ScNpl3) identified twoC. albicansproteins: CaNpl3, an apparent ScNpl3 ortholog, and Slr1, anotherSR-likeRNA-binding protein with no closeS. cerevisiaeortholog. Whereas ScNpl3 was critical for growth, deletion ofNPL3inC. albicansresulted in few phenotypic changes. In contrast, theslr1Δ/Δ mutant had a reduced growth ratein vitro, decreased filamentation, and impaired capacity to damage epithelial and endothelial cellsin vitro. Mice infected intravenously with theslr1Δ/Δ mutant strain had significantly prolonged survival compared to that of mice infected with the wild-type orslr1Δ/Δ mutant complemented withSLR1(slr1Δ/Δ+SLR1) strain, without a concomitant decrease in kidney fungal burden. Histopathology, however, revealed differential localization ofslr1Δ/Δ hyphal and yeast morphologies within the kidney. Mice infected withslr1Δ/Δ cells also had an increased brain fungal burden, which correlated with increased invasion of brain, but not umbilical vein, endothelial cellsin vitro. The enhanced brain endothelial cell invasion was likely due to the increased surface exposure of the Als3 adhesin onslr1Δ/Δ cells. Our results indicate that Slr1 is an SR-like protein that influencesC. albicansgrowth, filamentation, host cell interactions, and virulence.

scholarly journals The 5′ Untranslated Region of theEFG1Transcript Promotes Its Translation To Regulate Hyphal Morphogenesis inCandida albicans

mSphere ◽  
2018 ◽  
Vol 3 (4) ◽  
Author(s):  
Prashant R. Desai ◽  
Klaus Lengeler ◽  
Mario Kapitan ◽  
Silas Matthias Janßen ◽  
Paula Alepuz ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogen ◽  
Untranslated Regions ◽  
Regulatory Sequence ◽  
Transcriptional Level ◽  
Content Type ◽  
Reading Frame ◽  
Human Fungal Pathogen ◽  
Hyphal Morphogenesis ◽  
Incandida Albicans

ABSTRACTExtensive 5′ untranslated regions (UTR) are a hallmark of transcripts determining hyphal morphogenesis inCandida albicans. The major transcripts of theEFG1gene, which are responsible for cellular morphogenesis and metabolism, contain a 5′ UTR of up to 1,170 nucleotides (nt). Deletion analyses of the 5′ UTR revealed a 218-nt sequence that is required for production of the Efg1 protein and its functions in filamentation, without lowering the level and integrity of theEFG1transcript. Polysomal analyses revealed that the 218-nt 5′ UTR sequence is required for efficient translation of the Efg1 protein. Replacement of theEFG1open reading frame (ORF) by the heterologous reporter geneCaCBGlucconfirmed the positive regulatory importance of the identified 5′ UTR sequence. In contrast to other reported transcripts containing extensive 5′ UTR sequences, these results indicate the positive translational function of the 5′ UTR sequence in theEFG1transcript, which is observed in the context of the nativeEFG1promoter. It is proposed that the 5′ UTR recruits regulatory factors, possibly during emergence of the native transcript, which aid in translation of theEFG1transcript.IMPORTANCEMany of the virulence traits that makeCandida albicansan important human fungal pathogen are regulated on a transcriptional level. Here, we report an important regulatory contribution of translation, which is exerted by the extensive 5′ untranslated regulatory sequence (5′ UTR) of the transcript for the protein Efg1, which determines growth, metabolism, and filamentation in the fungus. The presence of the 5′ UTR is required for efficient translation of Efg1, to promote filamentation. Because transcripts for many relevant regulators contain extensive 5′ UTR sequences, it appears that the virulence ofC. albicansdepends on the combination of transcriptional and translational regulatory mechanisms.

scholarly journals A Candida albicans Temperature-Sensitivecdc12-6Mutant Identifies Roles for Septins in Selection of Sites of Germ Tube Formation and Hyphal Morphogenesis

2012 ◽  
Vol 11 (10) ◽  
pp. 1210-1218 ◽  
Author(s):  
Lifang Li ◽  
Chengda Zhang ◽  
James B. Konopka
Keyword(s):  
Candida Albicans ◽  
Germ Tube ◽  
Leading Edge ◽  
Hyphal Growth ◽  
Striking Difference ◽  
Temperature Sensitive ◽  
Content Type ◽  
Hyphal Morphogenesis ◽  
Germ Tubes ◽  
Selection Of

ABSTRACTSeptins were identified for their role in septation inSaccharomyces cerevisiaeand were subsequently implicated in other morphogenic processes. To study septins inCandida albicanshyphal morphogenesis, a temperature-sensitive mutation was created that altered the C terminus of the essential Cdc12 septin. Thecdc12-6cells grew well at room temperature, but at 37°C they displayed expected defects in septation, nuclear localization, and bud morphogenesis. Although serum stimulated thecdc12-6cells at 37°C to form germ tube outgrowths, the mutant could not maintain polarized hyphal growth and instead formed chains of elongated cell compartments. Serum also stimulated thecdc12-6mutant to induce a hyphal reporter gene (HWP1-GFP) and a characteristic zone of filipin staining at the leading edge of growth. Interestingly,cdc12-6cells shifted to 37°C in the absence of serum gradually displayed enriched filipin staining at the tip, which may be due to the altered cell cycle regulation. A striking difference from the wild type was that thecdc12-6cells frequently formed a second germ tube in close proximity to the first. The mutant cells also failed to form the diffuse band of septins at the base of germ tubes and hyphae, indicating that this septin band plays a role in preventing proximal formation of germ tubes in a manner analogous to bud site selection. These studies demonstrate that not only are septins important for cytokinesis, but they also promote polarized morphogenesis and selection of germ tube sites that may help disseminate an infection in host tissues.

scholarly journals The NDR Kinase Cbk1 Downregulates the Transcriptional Repressor Nrg1 through the mRNA-Binding Protein Ssd1 in Candida albicans

2015 ◽  
Vol 14 (7) ◽  
pp. 671-683 ◽  
Author(s):  
Hye-Jeong Lee ◽  
Jong-Myeong Kim ◽  
Woo Kyu Kang ◽  
Heebum Yang ◽  
Jeong-Yoon Kim
Keyword(s):  
Candida Albicans ◽  
Binding Protein ◽  
Transcriptional Repressor ◽  
Hyphal Growth ◽  
Content Type ◽  
Hyphal Morphogenesis ◽  
Essential Components ◽  
Mrna Binding Protein ◽  
Mrna Binding ◽  
Ndr Kinase

ABSTRACT NDR (nuclear Dbf2-related) kinases are essential components for polarized morphogenesis, cytokinesis, cell proliferation, and apoptosis. The NDR kinase Cbk1 is required for the hyphal growth of Candida albicans ; however, the molecular functions of Cbk1 in hyphal morphogenesis are largely unknown. Here, we report that Cbk1 downregulates the transcriptional repressor Nrg1 through the mRNA-binding protein Ssd1, which has nine Cbk1 phosphorylation consensus motifs. We found that deletion of SSD1 partially suppressed the defective hyphal growth of the C. albicans cbk1 Δ/Δ mutant and that Ssd1 physically interacts with Cbk1. Cbk1 was required for Ssd1 localization to polarized growth sites. The phosphomimetic SSD1 allele ( ssd1-9E ) allowed the cbk1 Δ/Δ mutant to form short hyphae, and the phosphodeficient SSD1 allele ( ssd1-9A ) resulted in shorter hyphae than did the wild-type SSD1 allele, indicating that Ssd1 phosphorylation by Cbk1 is important for hyphal morphogenesis. Furthermore, we show that the transcriptional repressor Nrg1 does not disappear during hyphal initiation in the cbk1 Δ/Δ mutant but is completely absent in the cbk1 Δ/Δ ssd1 Δ/Δ double mutant. Deletion of SSD1 also increased Als3 expression and internalization of the cbk1 Δ/Δ mutant in the human embryonic kidney cell line HEK293T. Collectively, our results suggest that one of the functions of Cbk1 in the hyphal morphogenesis of C. albicans is to downregulate Nrg1 through Ssd1.

scholarly journals Paradoxical Growth of Candida albicans in the Presence of Caspofungin Is Associated with Multiple Cell Wall Rearrangements and Decreased Virulence

2013 ◽  
Vol 58 (2) ◽  
pp. 1071-1083 ◽  
Author(s):  
Cristina Rueda ◽  
Manuel Cuenca-Estrella ◽  
Oscar Zaragoza
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Galleria Mellonella ◽  
Morphological Changes ◽  
Antifungal Drugs ◽  
Proinflammatory Response ◽  
Content Type ◽  
Multiple Cell ◽  
Fungal Adaptation ◽  
Paradoxical Growth

ABSTRACTIn the last decade, echinocandins have emerged as an important family of antifungal drugs because of their fungicidal activity againstCandidaspp. Echinocandins inhibit the enzyme β-1,3-d-glucan synthase, encoded by theFKSgenes, and resistance to echinocandins is associated with mutations in this gene. In addition, echinocandin exposure can produce paradoxical growth, defined as the ability to grow at high antifungal concentrations but not at intermediate concentrations. In this work, we have demonstrated that paradoxical growth ofCandida albicansin the presence of caspofungin is not due to antifungal degradation or instability. Media with high caspofungin concentrations recovered from wells whereC. albicansshowed paradoxical growth inhibited the growth of aCandida kruseireference strain. Cells exhibiting paradoxical growth at high caspofungin concentrations showed morphological changes such as enlarged size, abnormal septa, and absence of filamentation. Chitin content increased from the MIC to high caspofungin concentrations. Despite the high chitin levels, around 23% of cells died after treatment with caspofungin, indicating that chitin is required but not sufficient to protect the cells from the fungicidal effect of caspofungin. Moreover, we found that after paradoxical growth, β-1,3-glucan was exposed at the cell wall surface. Cells grown at high caspofungin concentrations had decreased virulence in the invertebrate hostGalleria mellonella. Cells grown at high caspofungin concentrations also induced a proinflammatory response in murine macrophages compared to control cells. Our work highlights important aspects about fungal adaptation to caspofungin, and although this adaptation is associated with reduced virulence, the clinical implications remain to be elucidated.

scholarly journals Candida albicans INT1-Induced Filamentation in Saccharomyces cerevisiae Depends on Sla2p

2001 ◽  
Vol 21 (4) ◽  
pp. 1272-1284 ◽  
Author(s):  
Catherine M. Asleson ◽  
Eric S. Bensen ◽  
Cheryl A. Gale ◽  
A.-S. Melms ◽  
Cornelia Kurischko ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Candida Albicans ◽  
Hyphal Growth ◽  
Filamentous Growth ◽  
Small Subset ◽  
Polarized Growth ◽  
Epistasis Analysis ◽  
Hyphal Morphogenesis ◽  
C Terminus ◽  
Important Virulence Factor

ABSTRACT The Candida albicans INT1 gene is important for hyphal morphogenesis, adherence, and virulence (C. Gale, C. Bendel, M. McClellan, M. Hauser, J. M. Becker, J. Berman, and M. Hostetter, Science 279:1355–1358, 1998). The ability to switch between yeast and hyphal morphologies is an important virulence factor in this fungal pathogen. When INT1 is expressed in Saccharomyces cerevisiae, cells grow with a filamentous morphology that we exploited to gain insights into how C. albicans regulates hyphal growth. In S. cerevisiae, INT1-induced filamentous growth was affected by a small subset of actin mutations and a limited set of actin-interacting proteins including Sla2p, anS. cerevisiae protein with similarity in its C terminus to mouse talin. Interestingly, while SLA2 was required forINT1-induced filamentous growth, it was not required for polarized growth in response to several other conditions, suggesting that Sla2p is not required for polarized growth per se. The morphogenesis checkpoint, mediated by Swe1p, contributes toINT1-induced filamentous growth; however, epistasis analysis suggests that Sla2p and Swe1p contribute toINT1-induced filamentous growth through independent pathways. The C. albicans SLA2 homolog (CaSLA2) complements S. cerevisiae sla2Δ mutants for growth at 37°C and INT1-induced filamentous growth. Furthermore, in a C. albicans Casla2/Casla2 strain, hyphal growth did not occur in response to either nutrient deprivation or to potent stimuli, such as mammalian serum. Thus, through analysis ofINT1-induced filamentous growth in S. cerevisiae, we have identified a C. albicans gene,SLA2, that is required for hyphal growth in C. albicans.

scholarly journals Control of Polarized Growth by the Rho Family GTPase Rho4 in Budding Yeast: Requirement of the N-Terminal Extension of Rho4 and Regulation by the Rho GTPase-Activating Protein Bem2

2012 ◽  
Vol 12 (2) ◽  
pp. 368-377 ◽  
Author(s):  
Ting Gong ◽  
Yuan Liao ◽  
Fei He ◽  
Yang Yang ◽  
Dan-Dan Yang ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Rho Gtpase ◽  
Budding Yeast ◽  
Bimolecular Fluorescence Complementation ◽  
Growth Defect ◽  
Temperature Sensitive ◽  
Polarized Growth ◽  
Gtpase Activating Protein ◽  
Content Type ◽  
Morphological Defects

ABSTRACT In the budding yeast Saccharomyces cerevisiae , Rho4 GTPase partially plays a redundant role with Rho3 in the control of polarized growth, as deletion of RHO4 and RHO3 together, but not RHO4 alone, caused lethality and a loss of cell polarity at 30°C. Here, we show that overexpression of the constitutively active rho4 Q131L mutant in an rdi1 Δ strain caused a severe growth defect and generated large, round, unbudded cells, suggesting that an excess of Rho4 activity could block bud emergence. We also generated four temperature-sensitive rho4-Ts alleles in a rho3 Δ rho4 Δ strain. These mutants showed growth and morphological defects at 37°C. Interestingly, two rho4-Ts alleles contain mutations that cause amino acid substitutions in the N-terminal region of Rho4. Rho4 possesses a long N-terminal extension that is unique among the six Rho GTPases in the budding yeast but is common in Rho4 homologs in other yeasts and filamentous fungi. We show that the N-terminal extension plays an important role in Rho4 function since rho3 Δ rho4 Δ 61 cells expressing truncated Rho4 lacking amino acids (aa) 1 to 61 exhibited morphological defects at 24°C and a growth defect at 37°C. Furthermore, we show that Rho4 interacts with Bem2, a Rho GTPase-activating protein (RhoGAP) for Cdc42 and Rho1, by yeast two-hybrid, bimolecular fluorescence complementation (BiFC), and glutathione S -transferase (GST) pulldown assays. Bem2 specifically interacts with the GTP-bound form of Rho4, and the interaction is mediated by its RhoGAP domain. Overexpression of BEM2 aggravates the defects of rho3 Δ rho4 mutants. These results suggest that Bem2 might be a novel GAP for Rho4.

scholarly journals Regulation of the Candida albicans Hypha-Inducing Transcription Factor Ume6 by the CDK1 Cyclins Cln3 and Hgc1

mSphere ◽  
2017 ◽  
Vol 2 (2) ◽  
Author(s):  
Sigal Mendelsohn ◽  
Mariel Pinsky ◽  
Ziva Weissman ◽  
Daniel Kornitzer
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Candida Albicans ◽  
Fungal Pathogen ◽  
Molecular Basis ◽  
Yeast Cells ◽  
Industrialized Countries ◽  
Content Type ◽  
Hyphal Morphogenesis ◽  
Multicellular Organisms

ABSTRACT The yeast to hypha (mold) morphogenetic switch of Candida albicans plays a role in its virulence and constitutes a diagnostic trait for this organism, the most prevalent systemic fungal pathogen in industrialized countries. It has long been known that hyphae are most efficiently induced from stationary cultures. Here, a molecular basis for this observation is provided. The G1 cyclin Cln3, an essential promoter of yeast proliferation, was found to suppress hyphal induction. Suppression of hyphal induction is achieved by inhibition of the activity of the central activator of hyphal morphogenesis, the transcription factor Ume6. Thus, levels of Cln3 control the switch between proliferation of C. albicans as individual yeast cells and development into extended hyphae, a switch that may preface the proliferation/differentiation switch in multicellular organisms. The ability to switch between proliferation as yeast cells and development into hyphae is a hallmark of Candida albicans. The switch to hyphal morphogenesis depends on external inducing conditions, but its efficiency is augmented in stationary-phase cells. Ume6, a transcription factor that is itself transcriptionally induced under hypha-promoting conditions, is both necessary and sufficient for hyphal morphogenesis. We found that Ume6 is regulated posttranslationally by the cell cycle kinase Cdc28/Cdk1, which reduces Ume6 activity via different mechanisms using different cyclins. Together with the cyclin Hgc1, Cdk1 promotes degradation of Ume6 via the SCFCDC4 ubiquitin ligase. Since HGC1 is a key transcriptional target of Ume6, this results in a negative-feedback loop between Hgc1 and Ume6. In addition, we found that Cln3, a G1 cyclin that is essential for cell cycle progression and yeast proliferation, suppresses hyphal morphogenesis and that Cln3 suppresses Ume6 activity both in the heterologous Saccharomyces cerevisiae system and in C. albicans itself. This activity of Cln3 may provide the basis for the antagonistic relationship between yeast proliferation and hyphal development in C. albicans. IMPORTANCE The yeast to hypha (mold) morphogenetic switch of Candida albicans plays a role in its virulence and constitutes a diagnostic trait for this organism, the most prevalent systemic fungal pathogen in industrialized countries. It has long been known that hyphae are most efficiently induced from stationary cultures. Here, a molecular basis for this observation is provided. The G1 cyclin Cln3, an essential promoter of yeast proliferation, was found to suppress hyphal induction. Suppression of hyphal induction is achieved by inhibition of the activity of the central activator of hyphal morphogenesis, the transcription factor Ume6. Thus, levels of Cln3 control the switch between proliferation of C. albicans as individual yeast cells and development into extended hyphae, a switch that may preface the proliferation/differentiation switch in multicellular organisms.

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