N-acetylglucosamine (GlcNAc) functions in cell signaling

Abstract

The amino sugar N-acetylglucosamine (GlcNAc) is well known for the important structural roles that it plays at the cell surface. It is a key component of bacterial cell wall peptidoglycan, fungal cell wall chitin, and the extracellular matrix of animal cells. Interestingly, recent studies have also identified new roles for GlcNAc in cell signaling. For example, GlcNAc stimulates the human fungal pathogen Candida albicans to undergo changes in morphogenesis and expression of virulence genes. Pathogenic E. coli respond to GlcNAc by altering the expression of fimbriae and CURLI fibers that promote biofilm formation and GlcNAc stimulates soil bacteria to undergo changes in morphogenesis and production of antibiotics. Studies with animal cells have revealed that GlcNAc influences cell signaling through the post-translational modification of proteins by glycosylation. O-linked attachment of GlcNAc to Ser and Thr residues regulates a variety of intracellular proteins, including transcription factors such as NFκB, c-myc and p53. In addition, the specificity of Notch family receptors for different ligands is altered by GlcNAc attachment to fucose residues in the extracellular domain. GlcNAc also impacts signal transduction by altering the degree of branching of N-linked glycans, which influences cell surface signaling proteins. These emerging roles of GlcNAc as an activator and mediator of cellular signaling in fungi, animals, and bacteria will be the focus of this review.

Figure 1

GlcNAc synthesis and degradation pathways in C. albicans.

Figure 2

Comparison of GlcNAc synthesis pathways in fungi and bacteria. C. albicans and bacteria such as E. coli are thought to sense forms of GlcNAc (shown in red) that are not intermediates in the cellular hexosamine synthesis pathway. De novo synthesis pathways for GlcNAc are shown in black.

Figure 3

NAG regulon in C. albicans.The C. albicans HXK1, NAG1, and DAC1 genes are clustered on chromosome 6 as shown in the figure.

Figure 4

Regulation of GlcNAc synthesis and catabolic genes in E. coli. The upper image illustrates the regulation of the GlcNAc catabolic genes and the lower panel shows the GlcNAc synthesis genes. Note that the NagC transcriptional regulator acts as a repressor of the nagABCDE operon but is an activator of the glmUS operon. Binding of GlcNAc-6-PO₄ alters NagC so that the expression of the GlcNAc catabolic genes (nagABCDE) is increased and the expression of the synthesis genes (glmUS) is decreased. (Note: gene sizes are not drawn to scale in order to present NagC regulation more clearly.)