Role of Transcription Factor CaNdt80p in Cell Separation, Hyphal Growth, and Virulence in Candida albicans

Abstract

The NDT80/PhoG transcription factor family includes ScNdt80p, a key modulator of the progression of meiotic division in Saccharomyces cerevisiae. In Candida albicans, a member of this family, CaNdt80p, modulates azole sensitivity by controlling the expression of ergosterol biosynthesis genes. We previously demonstrated that CaNdt80p promoter targets, in addition to ERG genes, were significantly enriched in genes related to hyphal growth. Here, we report that CaNdt80p is indeed required for hyphal growth in response to different filament-inducing cues and for the proper expression of genes characterizing the filamentous transcriptional program. These include noteworthy genes encoding cell wall components, such as HWP1, ECE1, RBT4, and ALS3. We also show that CaNdt80p is essential for the completion of cell separation through the direct transcriptional regulation of genes encoding the chitinase Cht3p and the cell wall glucosidase Sun41p. Consistent with their hyphal defect, ndt80 mutants are avirulent in a mouse model of systemic candidiasis. Interestingly, based on functional-domain organization, CaNdt80p seems to be a unique regulator characterizing fungi from the CTG clade within the subphylum Saccharomycotina. Therefore, this study revealed a new role of the novel member of the fungal NDT80 transcription factor family as a regulator of cell separation, hyphal growth, and virulence.

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

“…Ndt80p occupies the promoter region of roughly a quarter of total C. albicans genes under yeast-form growth conditions, suggesting wide functions for Ndt80p [57]. Indeed, it was shown that Ndt80p regulates different processes including drug resistance, cell separation, hyphal differentiation, biofilm formation and virulence [54,57,58]. Importantly, the C. albicans ndt80D/ndt80D mutant is unable to form true hyphae under different filamentation-inducing conditions and, in the presence of serum at 37uC, it fails to activate the expression of HSGs, including HWP1, ECE1, RBT4, ALS3, HYR1 and SAP4 [58], all directly regulated by Sfl2p (Figure 6), as well as the transcription factor-encoding genes TEC1 and UME6 which are both directly modulated by Sfl1p and Sfl2p ( Figure 6).…”

“…Indeed, it was shown that Ndt80p regulates different processes including drug resistance, cell separation, hyphal differentiation, biofilm formation and virulence [54,57,58]. Importantly, the C. albicans ndt80D/ndt80D mutant is unable to form true hyphae under different filamentation-inducing conditions and, in the presence of serum at 37uC, it fails to activate the expression of HSGs, including HWP1, ECE1, RBT4, ALS3, HYR1 and SAP4 [58], all directly regulated by Sfl2p (Figure 6), as well as the transcription factor-encoding genes TEC1 and UME6 which are both directly modulated by Sfl1p and Sfl2p ( Figure 6). Additionally, under the same growth conditions, the homozygous ndt80 mutant was unable to downregulate the yeast form-associated genes YWP1, RHD3, RHD1 and the transcriptional repressorencoding gene NRG1 [58], which are also direct targets of Sfl1p or Sfl2p ( Figure 6).…”

“…Importantly, the C. albicans ndt80D/ndt80D mutant is unable to form true hyphae under different filamentation-inducing conditions and, in the presence of serum at 37uC, it fails to activate the expression of HSGs, including HWP1, ECE1, RBT4, ALS3, HYR1 and SAP4 [58], all directly regulated by Sfl2p (Figure 6), as well as the transcription factor-encoding genes TEC1 and UME6 which are both directly modulated by Sfl1p and Sfl2p ( Figure 6). Additionally, under the same growth conditions, the homozygous ndt80 mutant was unable to downregulate the yeast form-associated genes YWP1, RHD3, RHD1 and the transcriptional repressorencoding gene NRG1 [58], which are also direct targets of Sfl1p or Sfl2p ( Figure 6). These observations, together with our findings that i) Ndt80p binding motif was enriched among Sfl1p and Sfl2p bound sequences and that ii) a significant proportion of its genome-wide binding profile overlapped with Sfl1p and Sfl2p binding, suggest that Sfl1p, Sfl2p and Ndt80p cooperatively regulate C. albicans morphogenesis in response to temperature variation.…”

“…2log 10 E-value) .10 for RSAT analyses and .25 for SCOPE analyses). Ndt80p is a transcription factor that controls the expression of genes involved in many cellular processes, including drug resistance, cell separation, morphogenesis and virulence through the recognition of mid-sporulation elements on the promoter of its targets [57,58].…”

Meiotic Regulators Ndt80 and Ime2 Have Different Roles in Saccharomyces and Neurospora

“…In C. albicans, CaNdt80 controls the expression of CDR1, a drug efflux pump that contributes to resistance against certain antifungal compounds (Chen et al 2004), in addition to genes involved in filamentous growth (Sellam et al 2009(Sellam et al , 2010. Like many other NDT80 homologs, including those in N. crassa, the DNA-binding domain of CaNdt80 is similar to Ndt80, but the rest of the protein is divergent (Wang et al 2006).…”