N-Acetylglucosamine (GlcNAc) Sensing, Utilization, and Functions in Candida albicans

Abstract

The sensing and efficient utilization of environmental nutrients are critical for the survival of microorganisms in environments where nutrients are limited, such as within mammalian hosts. Candida albicans is a common member of the human microbiota as well as an opportunistic fungal pathogen. The amide derivative sugar N-acetlyglucosamine (GlcNAc) is an important signaling molecule for C. albicans that could be a major nutrient source for this fungus in host settings. In this article, we review progress made over the past two decades on GlcNAc utilization, sensing, and functions in C. albicans and its related fungal species. GlcNAc sensing and catabolic pathways have been intensively studied in C. albicans. The C. albicans protein Ngt1 represents the first identified GlcNAc-specific transporter in eukaryotic organisms. In C. albicans, GlcNAc not only induces morphological transitions including the yeast to hyphal transition and the white to opaque phenotypic switch, but it also promotes fungal cell death. The Ras-cAMP/PKA signaling pathway plays critical roles in regulating these processes. Given the importance of GlcNAc sensing and utilization in C. albicans, targeting GlcNAc associated pathways and key pathway components could be promising in the development of new antifungal strategies.

Keywords: Candida albicans; GlcNAc; GlcNAc utilization; N-acetylglucosamine; Ngt1; cAMP signaling; cell surface receptor; morphological transitions; virulence.

Figure 1

N-acetlyglucosamine (GlcNAc) catabolism in Candida albicans. Ngt1, GlcNAc-specific transporter; Hxk1, GlcNAc kinase; Dac1, GlcNAc-6-phosphate deacetylase; Nag1, Glucosamine-6-phosphate deaminase; Ngs1, N-acetyltransferase; Rep1, transcription factor involved in transcription of GlcNAc-inducible genes. GlcNAc is transported into the cytoplasm by the Ngt1 transporter and is catabolized to fructose-6-phosphate by Hxk1, Dac1, and Nag1. Ngs1 can bind to GlcNAc and may function as a putative sensor. Together with the transcription factor, Rep1, Ngs1 induces the expression of GlcNAc-catabolic genes in the presence of GlcNAc.

Figure 2

The Ras1-cAMP/PKA signaling pathway regulates GlcNAc-induced filamentation and white–opaque switching in C. albicans. GlcNAc may directly activate the small GTPase Ras1. Activated Ras1 stimulates the adenylyl cyclase Cyr1 to produce cAMP, while the cyclic nucleotide phosphodiesterase Pde2 degrades cAMP. In the absence of GlcNAc, the PKA regulatory subunit Bcy1 binds to the catalytic subunits Tpk1 and Tpk2. In the presence of GlcNAc, cAMP binds to Bcy1 and leads to the release and activation of the catalytic subunits that subsequently phosphorylates filamentation-specific or opaque-specific regulators.