Candida albicans Ume6, a Filament-Specific Transcriptional Regulator, Directs Hyphal Growth via a Pathway Involving Hgc1 Cyclin-Related Protein

Abstract

The ability of Candida albicans, the most common human fungal pathogen, to transition from yeast to hyphae is essential for pathogenicity. While a variety of transcription factors important for filamentation have been identified and characterized, links between transcriptional regulators of C. albicans morphogenesis and molecular mechanisms that drive hyphal growth are not well defined. We have previously observed that constitutive expression of UME6, which encodes a filament-specific transcriptional regulator, is sufficient to direct hyphal growth in the absence of filament-inducing conditions. Here we show that HGC1, encoding a cyclinrelated protein necessary for hyphal growth under filament-inducing conditions, is specifically important for agar invasion, hyphal extension, and formation of true septa in response to constitutive UME6 expression under non-filament-inducing conditions. HGC1-dependent inactivation of Rga2, a Cdc42 GTPase activating protein (GAP), also appears to be important for these processes. In response to filament-inducing conditions, HGC1 is induced prior to UME6 although UME6 controls the level and duration of HGC1 expression, which are likely to be important for hyphal extension. Interestingly, an epistasis analysis suggests that UME6 and HGC1 play distinct roles during early filament formation. These findings establish a link between a key regulator of filamentation and a downstream mechanism important for hyphal formation. In addition, this study demonstrates that a strain expressing constitutive high levels of UME6 provides a powerful strategy to specifically dissect downstream mechanisms important for hyphal development in the absence of complex filament-inducing conditions.

Expression of UME6 , a Key Regulator of Candida albicans Hyphal Development, Enhances Biofilm Formation via Hgc1- and Sun41-Dependent Mechanisms

“…Genotypes for all strains used in this study are shown in Table 1. The wild-type tetR control strain (PCY87) as well as tetO-UME6 (MBY38) and tetO-UME6 hgc1⌬/⌬ (PCY50) strains were described previously (34,37). In order to construct the tetO-UME6 efg1⌬/⌬ strain (PCY21), primer pairs 1/2 and 3/4 (see Table S1 in the supplemental material for a list of all primers used in this study) were used to generate PCR products corresponding to the 5= and 3= flanking regions (just outside the open reading frame), respectively, of EFG1.…”

“…Hgc1 is known to form a cyclin/Cdk complex with Cdc28 kinase, which, in turn, is important for septin phosphorylation, inhibition of cell separation, and activation of the Cdc42 master polarity regulator (involved in septin ring organization, vesicle transport to the hyphal tip, and actin polymerization) (38)(39)(40)(41)(42)(43)(44). Expression of UME6 in an hgc1⌬/⌬ mutant strain results in shorter filaments with constrictions at septal junctions (37). Although Hgc1 is directly involved in a variety of mechanisms important for driving C. albicans hyphal growth, a role for Hgc1 in biofilm formation has not yet been reported.…”

“…We have previously shown that UME6 drives hyphal development via transcriptional induction of HGC1, which encodes a cyclin-related protein (37). Hgc1 is known to form a cyclin/Cdk complex with Cdc28 kinase, which, in turn, is important for septin phosphorylation, inhibition of cell separation, and activation of the Cdc42 master polarity regulator (involved in septin ring organization, vesicle transport to the hyphal tip, and actin polymerization) (38)(39)(40)(41)(42)(43)(44).…”

Differential virulence of Candida albicansandC. dubliniensis: A role for Tor1 kinase?

“…1). 19,20 Addition of peptone to nutrient poor WS medium could sequentially decrease filament formation in C. dubliniensis and this was associated with a sequential decrease in UME6 expression (Fig. 1).…”

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

“…Hgc1 is a cyclin of the cyclin-dependent kinase Cdc28 and has an important function in hyphal development, as an hgc1 homozygous deletion mutant is defective in polarized growth and cell chain formation during filamentous growth (652). Hgc1 is also required for proper septa formation, hyphal extension, and agar invasion in filamentation induced by the constitutive expression of the transcriptional regulator UME6 (94). Cdc28 is also involved in morphogenesis, as the depletion of Cdc28 leads to filamentous growth and the expression of hypha-specific transcripts, such as HWP1 and ECE1 (590).…”