Regulation of Hyphal Growth and N-Acetylglucosamine Catabolism by Two Transcription Factors in Candida albicans

Abstract

The amino sugar N-acetylglucosamine (GlcNAc) is increasingly recognized as an important signaling molecule in addition to its well-known structural roles at the cell surface. In the human fungal pathogen Candida albicans, GlcNAc stimulates several responses including the induction of the genes needed for its catabolism and a switch from budding to filamentous hyphal growth. We identified two genes needed for growth on GlcNAc (RON1 and NGS1) and found that mutants lacking these genes fail to induce the genes needed for GlcNAc catabolism. NGS1 was also important for growth on other sugars, such as maltose, but RON1 appeared to be specific for GlcNAc. Both mutants could grow on nonfermentable carbon sources indicating that they do not affect mitochondrial function, which we show is important for growth on GlcNAc but not for GlcNAc induction of hyphal morphogenesis. Interestingly, both the ron1D and ngs1D mutants were defective in forming hyphae in response to GlcNAc, even though GlcNAc catabolism is not required for induction of hyphal morphogenesis. The ron1D mutant showed a partial defect in forming hyphae, which was surprising since it displayed an elevated level of filamentous cells under noninducing conditions. The ron1D mutant also displayed an elevated basal level of expression of genes that are normally upregulated during hyphal growth. Consistent with this, Ron1 contains an Ndt80-like DNA-binding domain, indicating that it regulates gene expression. Thus, Ron1 is a key new component of the GlcNAc response pathway that acts as both an activator and a repressor of hyphal morphogenesis.

Multiple Alternative Carbon Pathways Combine To Promote Candida albicans Stress Resistance, Immune Interactions, and Virulence

“…Engineered carbon-deficient mutants are impaired in multiple virulence models. As a second and more direct approach to address this issue, we employed the CRISPR-Cas9 system to generate strains lacking one or more of the genes that have been previously shown to directly contribute to nutrient import and catabolism, i.e., STP2, JEN1, JEN2, HXK1, NAG1, and DAC1 (11,29,32). Stp2 is a transcription factor that controls amino acid import and catabolism.…”

“…The plasma membrane SPS amino acid sensor (Ssy1, Ptr3, Ssy5) regulates Stp2 and has very similar macrophage phenotypes (67), but it is not clear whether sensing and metabolism can be decoupled. GlcNac sensing (by Ngs1) and import (through Ngt1) are required for hyphal induction (29), suggesting that catabolism may also be dispensable for GlcNAc-induced stress resistance. Separating nutrient sensing and catabolism for pathogenesis and stress resistance will provide new insights into how pathogenic fungi detect, interact with, and adapt to various host environments.…”

What Are the Functions of Chitin Deacetylases in Aspergillus fumigatus?

“…Two orthologs with 20-26% of homology have been identified in the A. fumigatus genome. Yet, no protein homology was observed between Cda7 and the GlcNAc sensors such as Ngs1, the GlcNAc deacetylase Nag2 which is part of the NAG regulon governing the GlcNAc signalization pathway in C. albicans, nor Gig1 (Su et al, 2016;Naseem et al, 2017). The production of recombinant Cda proteins of A. fumigatus, as well as the analysis of the expression of the different CDA's in presence of GlcNAc or GlcN will be required to elucidate the role of CDAs in A. fumigatus.…”

Hyphal induction under the condition without inoculation in Candida albicans is triggered by Brg1‐mediated removal of NRG1 inhibition

“…The effect of GlcNAc in hyphal induction is through a mechanism sensitive to inhibitors of cAMP-dependent protein kinase in C. albicans (Castilla et al, 1998), whereas only a normal basal level of cAMP, but not a pulse of cAMP-PKA activation, is needed (Parrino et al, 2017). Recent study reported that the GlcNAc-sensor and transducer Ngs1 is important for GlcNAc-induced hyphal development, especially hyphal transcription in log phase cells (Su et al, 2016;Naseem et al, 2017). The N-terminal b-N-acetylglucosaminidase homology domain in Ngs1 can bind GlcNAc, and this binding activates its C-terminal GCN5-related N-acetyltransferase (GNAT) domain.…”