UME6, a Novel Filament-specific Regulator ofCandida albicansHyphal Extension and Virulence

Abstract

The specific ability of the major human fungal pathogen Candida albicans, as well as many other pathogenic fungi, to extend initial short filaments (germ tubes) into elongated hyphal filaments is important for a variety of virulence-related processes. However, the molecular mechanisms that control hyphal extension have remained poorly understood for many years. We report the identification of a novel C. albicans transcriptional regulator, UME6, which is induced in response to multiple host environmental cues and is specifically important for hyphal extension. Although capable of forming germ tubes, the ume6⌬/ume6⌬ mutant exhibits a clear defect in hyphal extension both in vitro and during infection in vivo and is attenuated for virulence in a mouse model of systemic candidiasis. We also show that UME6 is an important downstream component of both the RFG1-TUP1 and NRG1-TUP1 filamentous growth regulatory pathways, and we provide evidence to suggest that Nrg1 and Ume6 function together by a negative feedback loop to control the level and duration of filament-specific gene expression in response to inducing conditions. Our results suggest that hyphal extension is controlled by a specific transcriptional regulatory mechanism and is correlated with the maintenance of high-level expression of genes in the C. albicans filamentous growth program.

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).…”

Candida albicansdimorphism as a therapeutic target

“…Less attention has been paid to factors that regulate the hyphal-to-yeast transition, such as the hyphal repressors Nrg1 or Tup1 [31][32][33], or to factors that are important for maintenance or extension of hyphal growth, for example Cln1, Pes1, Eed1 or Ume6 [34][35][36][37][38]. These factors not only govern morphology, but also regulate morphologyassociated genes, for example, HWP1, SOD5, SAP4-6 or ALS3, the expression of which is linked to hyphal growth under most conditions.…”

Fungal Morphogenesis

“…The combination of hypoxia and high CO 2 , but neither condition alone, maintains C. albicans hyphal elongation, even in mutants lacking the nutrient responsive chromatin-remodeling pathway . One key downstream target of Hda1-mediated chromatin regulation is Ume6, a hypha-specific transcription factor that controls the level and duration of hypha-specific transcription (Banerjee et al 2008;Carlisle et al 2009;Zeidler et al 2009;Lu et al 2012). Ume6 is stabilized via regulation by Ofd1, a prolyl hydroxylase family member that is inhibited by hypoxia and an uncharacterized pathway that senses high CO 2 .…”