Adaptation of the Efg1p Morphogenetic Pathway in Candida albicans by Negative Autoregulation and PKA-dependent Repression of the EFG1 Gene

Tebarth, Bernd; Doedt, Thomas; Krishnamurthy, Shankarling; Weide, Mirko; Monterola, Freida; Domínguez, Ángel; Ernst, Joachim F.

doi:10.1016/s0022-2836(03)00505-9

Cited by 82 publications

(127 citation statements)

References 35 publications

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“…The precipitated DNA was analyzed by PCR at Ϸ250 base pairs intervals across the whole promoters of hypha-specific genes. ACT1 served as a negative control as in previously published ChIP experiments (Tebarth et al, 2003). As shown in Figure 3A, a specific region from each of the hypha-specific promoters, Ϫ1350 to Ϫ1103 for ECE1, Ϫ1381 to Ϫ1101 for HWP1, and Ϫ424 to Ϫ290 for ALS3, was specifically detected from the Efg1-TAP ChIP compared with the control ChIP or the ACT1 promoter.…”

Section: Efg1 and The Nua4 Complex Are Present At The Uas Regions Of mentioning

confidence: 62%

Efg1-mediated Recruitment of NuA4 to Promoters Is Required for Hypha-specific Swi/Snf Binding and Activation inCandida albicans

Lü

Mao

et al. 2008

MBoC

102

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Efg1 is essential for hyphal development and virulence in the human pathogenic fungus Candida albicans. How Efg1 regulates gene expression is unknown. Here, we show that Efg1 interacts with components of the nucleosome acetyltransferase of H4 (NuA4) histone acetyltransferase (HAT) complex in both yeast and hyphal cells. Deleting YNG2, a subunit of the NuA4 HAT module, results in a significant decrease in the acetylation level of nucleosomal H4 and a profound defect in hyphal development, as well as a defect in the expression of hypha-specific genes. Using chromatin immunoprecipitation, Efg1 and the NuA4 complex are found at the UAS regions of hypha-specific genes in both yeast and hyphal cells, and Efg1 is required for the recruitment of NuA4. Nucleosomal H4 acetylation at the promoters peaks during initial hyphal induction in an Efg1-dependent manner. We also find that Efg1 bound to the promoters of hypha-specific genes is critical for recruitment of the Swi/Snf chromatin remodeling complex during hyphal induction. Our data show that the recruitment of the NuA4 complex by Efg1 to the promoters of hypha-specific genes is required for nucleosomal H4 acetylation at the promoters during hyphal induction and for subsequent binding of Swi/Snf and transcriptional activation. INTRODUCTIONCandida albicans has emerged as one of the most prevalent opportunistic fungal pathogens in humans. It causes mucosal as well as systemic candidiasis, especially in immunocompromised patients. C. albicans can undergo reversible morphogenetic transitions between budding yeast, pseudohyphal, and hyphal growth forms. Its unique ability to switch from yeast to hyphal growth in response to various signals is essential for its pathogenicity.Central to the yeast-to-hypha transition is the transcription factor Efg1, a member of the Asm1p, Phd1p, Sok2p, Efg1p, and StuAp (APSES) family of fungal proteins that regulate cellular differentiation in ascomycetes. Members of this family share a conserved DNA binding domain. Efg1 is an essential regulator of hyphal development, chlamydospore formation, and white-opaque phenotypic switching in C. albicans (Lo et al., 1997;Stoldt et al., 1997;Sonneborn et al., 1999;Srikantha et al., 2000;Zordan et al., 2007). It is suggested to function downstream of the cAMP/protein kinase A (PKA) pathway in hyphal development (Sonneborn et al., 2000;Bockmuhl and Ernst, 2001), and both Efg1 and PKA are required for the induction of hypha-specific genes. However, Efg1 also regulates other genes that are not modulated by the cAMP pathway (Sohn et al., 2003;Doedt et al., 2004;Harcus et al., 2004;Setiadi et al., 2006). Numerous in vitro and in vivo studies with efg1 mutants have demonstrated that Efg1 is important for C. albicans virulence and for the interactions of C. albicans with endothelial and epithelia cells, as well as biofilm formation and catheter infection (Lo et al., 1997;Phan et al., 2000;Dieterich et al., 2002;Lewis et al., 2002;Ramage et al., 2002;Garcia-Sanchez et al., 2004). Despite its importance, molecula...

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Section: Efg1 and The Nua4 Complex Are Present At The Uas Regions Of mentioning

confidence: 62%

Efg1-mediated Recruitment of NuA4 to Promoters Is Required for Hypha-specific Swi/Snf Binding and Activation inCandida albicans

Lü

Mao

et al. 2008

MBoC

102

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“…Efg1 is a central regulator of numerous cellular processes in C. albicans. Efg1 is required for development of true hyphae and has a dual role as a transcriptional activator and repressor, whose balanced activity is essential for pseudohyphal and hyphal morphogenesis of C. albicans (Stoldt et al, 1997;Tebarth et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor Efg1 contributes to the tolerance of Candida albicans biofilms against antifungal agents in vitro and in vivo

Bink

Govaert

Vandenbosch

et al. 2012

Journal of Medical Microbiology

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We investigated the molecular basis of the tolerance of Candida albicans biofilms to antifungals using the miconazole as a model compound, and translated the resulting data to other antifungals. Sessile cells of C. albicans Defg1, lacking the transcription factor Efg1, showed increased susceptibility to miconazole, amphotericin B and caspofungin, whereas these sessile cells were equally resistant to fluconazole. The increased sensitivity to miconazole was, at least, partly due to an increased accumulation of miconazole in the cells as compared to wild-type or reintegrant Defg1(EFG1) sessile cells. By using a rat biofilm model, we further confirmed the role of Efg1 in the tolerance of C. albicans biofilms to miconazole when grown in vivo.

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“…In contrast to Saccharomyces cerevisiae, adenylyl cyclase is not needed for growth of C. albicans and instead plays an essential role in promoting hyphal formation (Rocha et al, 2001). cAMP stimulation of protein kinase A results in phosphorylation of downstream targets, including the transcription factor Efg1, which is needed for hyphal growth (Stoldt et al, 1997;Tebarth et al, 2003). In addition, MAP kinase signaling activates the Cph1 transcription factor that is also involved in hyphal signaling (Lo et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Identification of anN-Acetylglucosamine Transporter That Mediates Hyphal Induction inCandida albicans

Álvarez

Konopka

2007

MBoC

127

171

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The sugar N-acetylglucosamine (GlcNAc) plays an important role in nutrient sensing and cellular regulation in a wide range of organisms from bacteria to humans. In the fungal pathogen Candida albicans, GlcNAc induces a morphological transition from budding to hyphal growth. Proteomic comparison of plasma membrane proteins from buds and from hyphae induced by GlcNAc identified a novel hyphal protein (Ngt1) with similarity to the major facilitator superfamily of transporters. An Ngt1-GFP fusion was detected in the plasma membrane after induction with GlcNAc, but not other related sugars. Ngt1-GFP was also induced by macrophage phagocytosis, suggesting a role for the GlcNAc response in signaling entry into phagolysosomes. NGT1 is needed for efficient GlcNAc uptake and for the ability to induce hyphae at low GlcNAc concentrations. High concentrations of GlcNAc could bypass the need for NGT1 to induce hyphae, indicating that elevated intracellular levels of GlcNAc induce hyphal formation. Expression of NGT1 in Saccharomyces cerevisiae promoted GlcNAc uptake, indicating that Ngt1 acts directly as a GlcNAc transporter. Transport mediated by Ngt1 was specific, as other sugars could not compete for the uptake of GlcNAc. Thus, Ngt1 represents the first eukaryotic GlcNAc transporter to be discovered. The presence of NGT1 homologues in the genome sequences of a wide range of eukaryotes from yeast to mammals suggests that they may also function in the cellular processes regulated by GlcNAc, including those that underlie important diseases such as cancer and diabetes. INTRODUCTIONN-acetylglucosamine (GlcNAc) is an amino sugar that carries out important roles in a broad range of cells from bacteria to humans. One aspect of GlcNAc function is to mediate cellular signaling. In bacteria, GlcNAc induces components that are important for colonization of human hosts, including fimbrins that mediate adhesion to host cells (Sohanpal et al., 2004), multidrug exporter genes (Hirakawa et al., 2006) and Curli fibers that promote biofilm formation (Barnhart et al., 2006). In mammals, GlcNAc is a key sensor of nutrient status that is involved in insulin signaling, cell cycle control, and other essential processes. Nutritional effects that lead to increased GlcNAc levels result in its conversion to UDP-GlcNAc and subsequent attachment to proteins on serine or threonine residues in a dynamic manner that is analogous to modification of proteins by phosphorylation (Slawson and Hart, 2003;Zachara and Hart, 2006). In fact, the interplay between O-GlcNAc modification and phosphorylation of proteins regulates many critical transcription factors, such as c-myc and p53 (Chou and Hart, 2001;Yang et al., 2006). O-GlcNAc modification also regulates other processes including proteosome function (Zachara and Hart, 2004). In addition to these regulatory roles, GlcNAc contributes to the N-linked glycosylation, glycophosphatidylinositol (GPI) anchor addition to proteins and is polymerized into chitin, which forms part of the fungal cell wall and the exoskele...

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Adaptation of the Efg1p Morphogenetic Pathway in Candida albicans by Negative Autoregulation and PKA-dependent Repression of the EFG1 Gene

Cited by 82 publications

References 35 publications

Efg1-mediated Recruitment of NuA4 to Promoters Is Required for Hypha-specific Swi/Snf Binding and Activation inCandida albicans

Efg1-mediated Recruitment of NuA4 to Promoters Is Required for Hypha-specific Swi/Snf Binding and Activation inCandida albicans

Transcription factor Efg1 contributes to the tolerance of Candida albicans biofilms against antifungal agents in vitro and in vivo

Identification of anN-Acetylglucosamine Transporter That Mediates Hyphal Induction inCandida albicans

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