N-acetylglucosamine Signaling: Transcriptional Dynamics of a Novel Sugar Sensing Cascade in a Model Pathogenic Yeast, Candida albicans

Abstract

The amino sugar, N-acetylglucosamine (GlcNAc), has emerged as an attractive messenger of signaling in the pathogenic yeast Candida albicans, given its multifaceted role in cellular processes, including GlcNAc scavenging, import and metabolism, morphogenesis (yeast to hyphae and white to opaque switch), virulence, GlcNAc induced cell death (GICD), etc. During signaling, the exogenous GlcNAc appears to adopt a simple mechanism of gene regulation by directly activating Ngs1, a novel GlcNAc sensor and transducer, at the chromatin level, to activate transcriptional response through the promoter acetylation. Ngs1 acts as a master regulator in GlcNAc signaling by regulating GlcNAc catabolic gene expression and filamentation. Ndt80-family transcriptional factor Rep1 appears to be involved in the recruitment of Ngs1 to GlcNAc catabolic gene promoters. For promoting filamentation, GlcNAc adopts a little modified strategy by utilizing a recently evolved transcriptional loop. Here, Biofilm regulator Brg1 takes up the key role, getting up-regulated by Ngs1, and simultaneously induces Hyphal Specific Genes (HSGs) expression by down-regulating NRG1 expression. GlcNAc kinase Hxk1 appears to play a prominent role in signaling. Recent developments in GlcNAc signaling have made C. albicans a model system to understand its role in other eukaryotes as well. The knowledge thus gained would assist in designing therapeutic interventions for the control of candidiasis and other fungal diseases.

N-Acetylglucosamine Sensing and Metabolic Engineering for Attenuating Human and Plant Pathogens

“…There is growing evidence that GlcNAc acts as an intracellular signaling molecule in signaling pathways that impact the virulence and survival of the pathogens in hosts such as Candida albicans [ 24 , 56 ]. The first report of GlcNAc as a signaling molecule was reported in the human fungal pathogen C. albicans .…”

Demystifying the O-GlcNAc Code: A Systems View

“…It is plausible that O-GlcNAcylation was evolutionally lost and substituted by different sugars (e.g., O-mannose) with similar functions in many other fungi. 179,183,186,187,190,191 2.3.3. O-GlcNAcylation in Plants.…”

“…It has been pretty clear that the orthologues of OGT and OGA are conspicuously absent from model fungi organisms such as S. cerevisiae , Schizosaccharomyces pombe , and Candida albicans . ,, Intriguingly, besides using the imported exogenous GlcNAc, UDP-GlcNAc can be de novo synthesized in such organisms. − These unique properties make such systems a great tool to produce O-GlcNAcylated proteins. For example, ectopic expression of sOGT (the short form of the human OGT) leads to the O-GlcNAcylation of over 400 proteins in yeast. , While coexpression of OGA induces the hydrolysis of these sugar modifications, suggesting that O-GlcNAc cycling can occur in yeast cells.…”

“…Certain fungi species (e.g., Histoplasma capsulatum ) may display functioning OGT/OGA orthologues and thus O-GlcNAcylation yet to be identified. It is plausible that O-GlcNAcylation was evolutionally lost and substituted by different sugars (e.g., O-mannose) with similar functions in many other fungi. ,,,,, …”

Allosteric regulation by c-di-AMP modulates a complete N-acetylglucosamine signaling cascade in Saccharopolyspora erythraea

“…The binding of c-di-AMP by DasR directly links c-di-AMP to GlcNAc signaling. Accumulated evidence suggests that the amino sugar GlcNAc not only acts as a very good alternative carbon and nitrogen source 17 – 20 but also as a potent inducer of signaling to stimulate the expression of its own catabolic genes and morphogenetic switch, which plays a multifaceted role in cellular processes 20 – 22 . In addition, GlcNAc stimulates cellular signaling in pathogenic fungi such as Candida albicans 22 .…”