Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans, is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi

Stoldt, Volker R.; Sonneborn, Anja; Leuker, Christoph E.; Ernst, Joachim F.

doi:10.1093/emboj/16.8.1982

Cited by 581 publications

(638 citation statements)

References 45 publications

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“…Consequently, the transition is highly regulated and involves multiple interconnected signalling pathways, including the cyclic AMP-dependent Protein Kinase A (cAMP-PKA, regarded as playing a central role in the control of morphogenesis), the Cph1p-mediated Mitogen-Activated Protein Kinase (MAPK) and the Rim101p-mediated pH cascade pathways, all of which positively regulate hyphal development through the modulation of the activity of transcription factors to control the expression of HSGs (see [13] for a recent review). These transcription factors include (among others) Efg1p/ Flo8p, acting downstream of cAMP-PKA [14][15][16][17][18][19][20], Tec1p [21] and Ume6p [22,23]. Hyphal morphogenesis is also subject to negative regulation mostly by the general corepressor Tup1p through interaction with the transcriptional repressors Nrg1p and Rfg1p [4,12,[24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

A comprehensive functional portrait of two heat shock factor-type transcriptional regulators involved in Candida albicans morphogenesis and virulence

Znaidi

Nesseir

Chauvel

et al. 2013

Journal de Mycologie Médicale

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Sfl1p and Sfl2p are two homologous heat shock factor-type transcriptional regulators that antagonistically control morphogenesis in Candida albicans, while being required for full pathogenesis and virulence. To understand how Sfl1p and Sfl2p exert their function, we combined genome-wide location and expression analyses to reveal their transcriptional targets in vivo together with the associated changes of the C. albicans transcriptome. We show that Sfl1p and Sfl2p bind to the promoter of at least 113 common targets through divergent binding motifs and modulate directly the expression of key transcriptional regulators of C. albicans morphogenesis and/or virulence. Surprisingly, we found that Sfl2p additionally binds to the promoter of 75 specific targets, including a high proportion of hyphal-specific genes (HSGs; HWP1, HYR1, ECE1, others), revealing a direct link between Sfl2p and hyphal development. Data mining pointed to a regulatory network in which Sfl1p and Sfl2p act as both transcriptional activators and repressors. Sfl1p directly represses the expression of positive regulators of hyphal growth (BRG1, UME6, TEC1, SFL2), while upregulating both yeast form-associated genes (RME1, RHD1, YWP1) and repressors of morphogenesis (SSN6, NRG1). On the other hand, Sfl2p directly upregulates HSGs and activators of hyphal growth (UME6, TEC1), while downregulating yeast form-associated genes and repressors of morphogenesis (NRG1, RFG1, SFL1). Using genetic interaction analyses, we provide further evidences that Sfl1p and Sfl2p antagonistically control C. albicans morphogenesis through direct modulation of the expression of important regulators of hyphal growth. Bioinformatic analyses suggest that binding of Sfl1p and Sfl2p to their targets occurs with the co-binding of Efg1p and/or Ndt80p. We show, indeed, that Sfl1p and Sfl2p targets are bound by Efg1p and that both Sfl1p and Sfl2p associate in vivo with Efg1p. Taken together, our data suggest that Sfl1p and Sfl2p act as central ''switch on/off'' proteins to coordinate the regulation of C. albicans morphogenesis.

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Section: Introductionmentioning

confidence: 99%

A comprehensive functional portrait of two heat shock factor-type transcriptional regulators involved in Candida albicans morphogenesis and virulence

Znaidi

Nesseir

Chauvel

et al. 2013

Journal de Mycologie Médicale

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“…Tpk1 and Tpk2 have distinct functions in hyphal development because their mutants have differential effects in different media (Bockmuhl et al, 2001;Cassola et al, 2004). One potential target of the cAMP/PKA pathway is Efg1, a basic helix-loop-helix protein similar to StuA of Aspergillus nidulans and Sok2 and Phd1 of S. cerevisiae (Stoldt et al, 1997). efg1/efg1 mutants are unable to form hyphae in all liquidinducing media (Stoldt et al, 1997), but the mutants show enhanced hyphal formation under embedded growth con-ditions (Giusani et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…One potential target of the cAMP/PKA pathway is Efg1, a basic helix-loop-helix protein similar to StuA of Aspergillus nidulans and Sok2 and Phd1 of S. cerevisiae (Stoldt et al, 1997). efg1/efg1 mutants are unable to form hyphae in all liquidinducing media (Stoldt et al, 1997), but the mutants show enhanced hyphal formation under embedded growth con-ditions (Giusani et al, 2002). Transcription profiling of cAMP signaling in C. albicans shows that Ras1 regulates a subset of Cdc35-regulated genes, but Efg1-regulated genes are distinct from those modulated by Cdc35 except for the class of genes induced during the yeast-to-hypha transition (Harcus et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The Flo8 Transcription Factor Is Essential for Hyphal Development and Virulence inCandida albicans

Cao

Lane

Raniga

et al. 2006

MBoC

202

255

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The transcription factor Flo8 is essential for filamentous growth in Saccharomyces cerevisiae and is regulated under the cAMP/protein kinase A (PKA) pathway. To determine whether a similar pathway/regulation exists in Candida albicans, we have cloned C. albicans FLO8 by its ability to complement S. cerevisiae flo8. Deleting FLO8 in C. albicans blocked hyphal development and hypha-specific gene expression. The flo8/flo8 mutant is avirulent in a mouse model of systemic infection. Genome-wide transcription profiling of efg1/efg1 and flo8/flo8 using a C. albicans DNA microarray suggests that Flo8 controls subsets of Efg1-regulated genes. Most of these genes are hypha specific, including HGC1 and IHD1. We also show that Flo8 interacts with Efg1 in yeast and hyphal cells by in vivo immunoprecipitation. Similar to efg1/efg1, flo8/flo8 and cdc35/cdc35 show enhanced hyphal growth under an embedded growth condition. Our results suggest that Flo8 may function downstream of the cAMP/PKA pathway, and together with Efg1, regulates the expression of hypha-specific genes and genes that are important for the virulence of C. albicans.

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“…Several signal-transduction pathways are known to play roles in growth-form selection (Liu, 2001;Berman and Sudbery, 2002). The cAMPprotein kinase A (PKA) pathway has a key role, because blocking it abolishes true hyphal growth under most experimental conditions (Lo et al, 1997;Stoldt et al, 1997;Rocha et al, 2001). Another important pathway contains a MAPkinase cascade that seems to have a more important role in regulating pseudohyphal than true hyphal growth (Liu et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Critical Role of DNA Checkpoints in Mediating Genotoxic-Stress–induced Filamentous Growth inCandida albicans

Shi

Wang

Zheng

et al. 2007

MBoC

119

198

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The polymorphic fungus Candida albicans switches from yeast to filamentous growth in response to a range of genotoxic insults, including inhibition of DNA synthesis by hydroxyurea (HU) or aphidicolin (AC), depletion of the ribonucleotidereductase subunit Rnr2p, and DNA damage induced by methylmethane sulfonate (MMS) or UV light (UV). Deleting RAD53, which encodes a downstream effector kinase for both the DNA-replication and DNA-damage checkpoint pathways, completely abolished the filamentous growth caused by all the genotoxins tested. Deleting RAD9, which encodes a signal transducer of the DNA-damage checkpoint, specifically blocked the filamentous growth induced by MMS or UV but not that induced by HU or AC. Deleting MRC1, the counterpart of RAD9 in the DNA-replication checkpoint, impaired DNA synthesis and caused cell elongation even in the absence of external genotoxic insults. Together, the results indicate that the DNA-replication/damage checkpoints are critically required for the induction of filamentous growth by genotoxic stress. In addition, either of two mutations in the FHA1 domain of Rad53p, G65A, and N104A, nearly completely blocked the filamentous-growth response but had no significant deleterious effect on cell-cycle arrest. These results suggest that the FHA domain, known for its ability to bind phosphopeptides, has an important role in mediating genotoxic-stress-induced filamentous growth and that such growth is a specific, Rad53p-regulated cellular response in C. albicans. INTRODUCTIONThe polymorphic fungus Candida albicans has proven to be a very useful model for the study of cell morphogenesis (Odds, 1994;Sudbery et al., 2004;Wightman et al., 2004;Zheng et al., 2004). This organism can switch between several morphological forms including yeast, pseudohyphae, and hyphae (Berman and Sudbery, 2002;Sudbery et al., 2004). The yeast-hypha transition has attracted much attention because of its established importance for infection and virulence (Csank et al., 1997;Lo et al., 1997;Gale et al., 1998;Gow et al., 2002;Zheng et al., 2004). Several signal-transduction pathways are known to play roles in growth-form selection (Liu, 2001;Berman and Sudbery, 2002). The cAMPprotein kinase A (PKA) pathway has a key role, because blocking it abolishes true hyphal growth under most experimental conditions (Lo et al., 1997;Stoldt et al., 1997;Rocha et al., 2001). Another important pathway contains a MAPkinase cascade that seems to have a more important role in regulating pseudohyphal than true hyphal growth (Liu et al., 1994). The two pathways control the transcription factors Efg1p and Cph1p, respectively, which activate the expression of hypha-specific genes for a suite of infection-related functions (Lane et al., 2001).A diverse range of environmental stimuli can induce C. albicans hyphal or pseudohyphal growth, such as serum, neutral pH, appropriate temperature, certain amino acids and sugars, and some synthetic growth media (Ernst, 2000;Sudbery et al., 2004). These conditions more-or-less mimic certain host c...

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Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans, is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi

Cited by 581 publications

References 45 publications

A comprehensive functional portrait of two heat shock factor-type transcriptional regulators involved in Candida albicans morphogenesis and virulence

A comprehensive functional portrait of two heat shock factor-type transcriptional regulators involved in Candida albicans morphogenesis and virulence

The Flo8 Transcription Factor Is Essential for Hyphal Development and Virulence inCandida albicans

Critical Role of DNA Checkpoints in Mediating Genotoxic-Stress–induced Filamentous Growth inCandida albicans

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