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N-acetylglucosamine Regulates Virulence Properties in Microbial Pathogens.

Naseem S, Konopka JB - PLoS Pathog. (2015)

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, United States of America.

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There is growing evidence that the sugar N-acetylglucosamine (GlcNAc) plays diverse roles in cell signaling pathways that impact the virulence properties of microbes and host cells... GlcNAc is already well known as a ubiquitous structural component at the cell surface that forms part of bacterial cell wall peptidoglycan, cell wall chitin in fungi and parasites, and extracellular matrix glycosaminoglycans of animal cells... GlcNAc also stimulates the expression of virulence genes, such as the adhesins that promote adherence to host cells and biofilm formation... Analysis of a C. albicans mutant lacking all three enzymes needed for GlcNAc catabolism (hxk1Δ nag1Δ dac1Δ) showed that the breakdown of this sugar was not needed for it to promote hyphal growth... Furthermore, analysis of this mutant also indicated that GlcNAc did not have to be converted to the important building block UDP-GlcNAc... However, the mutant cells could induce hyphal-specific genes when buffered to a higher pH (>5) that mimicked the effects of GlcNAc catabolism... Although alkaline pH can induce hyphal responses, the observed effects occurred at pH levels that were well below the levels required to induce hyphae, indicating that there is synergy between these pathways... These results are significant because they indicate that GlcNAc can stimulate hyphal morphogenesis independently of the induction of hyphal-specific genes, which had been linked to promoting the transition to filamentous growth... This type of synergy between GlcNAc and pH likely occurs with other species, as cells from bacteria to humans export excess nitrogen as ammonia... Thus, future studies must take care to distinguish between a direct role of GlcNAc in cell signaling and an indirect effect on the ambient pH... An important source of GlcNAc for cell signaling in many environments is due to release of this sugar during bacterial growth due to remodeling of cell wall peptidoglycan, which consists of alternating GlcNAc and N-acetylmuramic acid residues... Proper regulation of GlcNAc metabolism genes is significant, as it is important for colonization of the host by E. coli and Vibrio cholera, and for production of virulence factors and biofilms by the cariogenic bacterium Streptococcus mutans... GlcNAc has diverse effects in different bacteria by up-regulating or down-regulating virulence factors... Elevated UDP-GlcNAc increases O-GlcNAc modification of proteins and also increases N-GlcNAc branching on cell surface proteins, which changes cell signaling properties by altering the stability of receptors on the cell surface.

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GlcNAc signaling pathways.(A) C. albicans grown in dextrose form budding cells (top) whereas growth in GlcNAc induces them to switch to the filamentous hyphal form (bottom). (B) Summary of three types of GlcNAc-regulated pathways. GlcNAc itself can transduce a signal to induce hyphal growth in C. albicans (red arrow). Catabolism of GlcNAc releases excess ammonia whose export alkalinizes the extracellular pH and can synergize with GlcNAc to induce hyphal growth and gene expression (blue arrow). In mammals and some microbes conversion of GlcNAc to the building block UDP-GlcNAc promotes changes in O-GlcNAc modification of intracellular proteins and N-linked glycosylation of cell surface proteins (green arrow).
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ppat.1004947.g001: GlcNAc signaling pathways.(A) C. albicans grown in dextrose form budding cells (top) whereas growth in GlcNAc induces them to switch to the filamentous hyphal form (bottom). (B) Summary of three types of GlcNAc-regulated pathways. GlcNAc itself can transduce a signal to induce hyphal growth in C. albicans (red arrow). Catabolism of GlcNAc releases excess ammonia whose export alkalinizes the extracellular pH and can synergize with GlcNAc to induce hyphal growth and gene expression (blue arrow). In mammals and some microbes conversion of GlcNAc to the building block UDP-GlcNAc promotes changes in O-GlcNAc modification of intracellular proteins and N-linked glycosylation of cell surface proteins (green arrow).

Mentions: GlcNAc first attracted attention as a signaling molecule for fungi over 40 years ago, when it was discovered to induce a remarkable switch from budding to hyphal growth in the human pathogen Candida albicans (Fig 1A) [7]. GlcNAc was subsequently shown to induce filamentous growth in a diverse group of fungi [5]. Switching to filamentous hyphal morphology contributes to invasive growth of C. albicans in the host and influences the interaction with leukocytes [8]. GlcNAc also stimulates the expression of virulence genes, such as the adhesins that promote adherence to host cells and biofilm formation [5,8]. Although it is not clear whether GlcNAc plays a role in systemic candidiasis, it has been implicated in commensal growth in the mucosa of the GI tract [9]. Consistent with this, GlcNAc promotes an epigenetic switch in morphology from the “White Phase” to the “Opaque Phase,” which is better adapted to mucosal growth [10].


N-acetylglucosamine Regulates Virulence Properties in Microbial Pathogens.

Naseem S, Konopka JB - PLoS Pathog. (2015)

GlcNAc signaling pathways.(A) C. albicans grown in dextrose form budding cells (top) whereas growth in GlcNAc induces them to switch to the filamentous hyphal form (bottom). (B) Summary of three types of GlcNAc-regulated pathways. GlcNAc itself can transduce a signal to induce hyphal growth in C. albicans (red arrow). Catabolism of GlcNAc releases excess ammonia whose export alkalinizes the extracellular pH and can synergize with GlcNAc to induce hyphal growth and gene expression (blue arrow). In mammals and some microbes conversion of GlcNAc to the building block UDP-GlcNAc promotes changes in O-GlcNAc modification of intracellular proteins and N-linked glycosylation of cell surface proteins (green arrow).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520607&req=5

ppat.1004947.g001: GlcNAc signaling pathways.(A) C. albicans grown in dextrose form budding cells (top) whereas growth in GlcNAc induces them to switch to the filamentous hyphal form (bottom). (B) Summary of three types of GlcNAc-regulated pathways. GlcNAc itself can transduce a signal to induce hyphal growth in C. albicans (red arrow). Catabolism of GlcNAc releases excess ammonia whose export alkalinizes the extracellular pH and can synergize with GlcNAc to induce hyphal growth and gene expression (blue arrow). In mammals and some microbes conversion of GlcNAc to the building block UDP-GlcNAc promotes changes in O-GlcNAc modification of intracellular proteins and N-linked glycosylation of cell surface proteins (green arrow).
Mentions: GlcNAc first attracted attention as a signaling molecule for fungi over 40 years ago, when it was discovered to induce a remarkable switch from budding to hyphal growth in the human pathogen Candida albicans (Fig 1A) [7]. GlcNAc was subsequently shown to induce filamentous growth in a diverse group of fungi [5]. Switching to filamentous hyphal morphology contributes to invasive growth of C. albicans in the host and influences the interaction with leukocytes [8]. GlcNAc also stimulates the expression of virulence genes, such as the adhesins that promote adherence to host cells and biofilm formation [5,8]. Although it is not clear whether GlcNAc plays a role in systemic candidiasis, it has been implicated in commensal growth in the mucosa of the GI tract [9]. Consistent with this, GlcNAc promotes an epigenetic switch in morphology from the “White Phase” to the “Opaque Phase,” which is better adapted to mucosal growth [10].

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, United States of America.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

There is growing evidence that the sugar N-acetylglucosamine (GlcNAc) plays diverse roles in cell signaling pathways that impact the virulence properties of microbes and host cells... GlcNAc is already well known as a ubiquitous structural component at the cell surface that forms part of bacterial cell wall peptidoglycan, cell wall chitin in fungi and parasites, and extracellular matrix glycosaminoglycans of animal cells... GlcNAc also stimulates the expression of virulence genes, such as the adhesins that promote adherence to host cells and biofilm formation... Analysis of a C. albicans mutant lacking all three enzymes needed for GlcNAc catabolism (hxk1Δ nag1Δ dac1Δ) showed that the breakdown of this sugar was not needed for it to promote hyphal growth... Furthermore, analysis of this mutant also indicated that GlcNAc did not have to be converted to the important building block UDP-GlcNAc... However, the mutant cells could induce hyphal-specific genes when buffered to a higher pH (>5) that mimicked the effects of GlcNAc catabolism... Although alkaline pH can induce hyphal responses, the observed effects occurred at pH levels that were well below the levels required to induce hyphae, indicating that there is synergy between these pathways... These results are significant because they indicate that GlcNAc can stimulate hyphal morphogenesis independently of the induction of hyphal-specific genes, which had been linked to promoting the transition to filamentous growth... This type of synergy between GlcNAc and pH likely occurs with other species, as cells from bacteria to humans export excess nitrogen as ammonia... Thus, future studies must take care to distinguish between a direct role of GlcNAc in cell signaling and an indirect effect on the ambient pH... An important source of GlcNAc for cell signaling in many environments is due to release of this sugar during bacterial growth due to remodeling of cell wall peptidoglycan, which consists of alternating GlcNAc and N-acetylmuramic acid residues... Proper regulation of GlcNAc metabolism genes is significant, as it is important for colonization of the host by E. coli and Vibrio cholera, and for production of virulence factors and biofilms by the cariogenic bacterium Streptococcus mutans... GlcNAc has diverse effects in different bacteria by up-regulating or down-regulating virulence factors... Elevated UDP-GlcNAc increases O-GlcNAc modification of proteins and also increases N-GlcNAc branching on cell surface proteins, which changes cell signaling properties by altering the stability of receptors on the cell surface.

No MeSH data available.