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N-glycosylation: Less tumors, more T cells

Connections between receptor cell surface expression and N-glycan structure. Click here for a larger figure.

The mannoside N-acetylglucosamine (GlcNAc) transferase 5 (Mgat5) synthesizes tetraantennary N-glycans, and the study by Lau et al. in Cell attempted to explain the connection between N-glycan structure and receptor signaling (see here). By investigating the molecular consequences of Mgat5 ablation, the Demetriou and Dennis groups now elucidate the effects of N-glycan structure on T cell receptor signaling, fibroblast proliferation and mouse physiology in three follow-up studies.

Reporting to the Journal of Biological Chemistry, the authors examined the effect of nutrient sensing and N-glycosylation on T-cell proliferation and signaling. Mgat5^-/- T cells carried many fewer tetraantennary branched N-glycans than normal T cells. After immune stimulation, T-cell receptor (TCR) clustering was increased in the Mgat5^-/- T cells because the galectin/N-glycan lattice was weakened. Enhanced TCR clustering led to drastically increased TCR signalling, T_H1 helper cell differentiation and endocytosis of a T cell proliferation limiting receptor (CTLA-4). However, addition of hexosamine pathway metabolites to the cell medium (such as GlcNAc, uridine or glucose) caused formation of higher branched N-glycans and had the opposite effects of Mgat5 ablation in T cells. GlcNAc supplementation also slowed the development of multiple sclerosis in a mouse model of the disease, and impeded the development of diabetes in nonobese diabetic (NOD) mice. These observations open a new avenue for a metabolic treatment of autoimmune diseases.

Additional insight into the influence of N-glycan branching on growth factor receptor  signaling was provided in two recent Glycobiology studies by Dennis and colleagues. The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is activated downstream of activated growth factor receptor kinases such as PDGFR (platelet-derived growth factor receptor), while  basal or low endogenous activity of the PI3K/Akt pathway is maintained by phosphatase and tensin homolog (Pten) activity. Therefore, Pten^+/- mouse embryonic fibroblasts (MEFs) exhibit increased Akt phosphorylation and pathway activation and rapid cellular proliferation. Importantly, the authors found that Mgat5^-/-Pten^+/- double mutant MEFs exhibited normal levels of phospho-AKT and cellular proliferation. These results suggested that reduced N-glycan branching of growth receptors dampens the effects of enhanced PI3K/Akt signaling in Pten heterozygous cells. Moreover, Pten^+/- MEFs displayed increased expression of Mgat5  N-glycan products demonstrating positive feedback between the growth promoting effects of PI3K/Akt and the branched N-glycans. Accordingly, the overexpression of Mgat5 and PI3K in many types of cancer leads to enhanced sensitivity to growth factors,  cell motility and cancer cell invasion.

Metabolic and physiological effects of a genetic deletion of Mgat5 were investigated in the second Glycobiology study. Dennis and colleagues found that lack of Mgat5 increased glucose and fat catabolism, which was mirrored by lower leptin and higher glucagon levels. However, the numbers of osteoblast and satellite stem cells which renew bone and muscle tissues were lower in the mutant mice. The reduction of renewable cell populations was accompanied by increased TGF- (transforming growth factor-) and reduced PDGFR-signaling via the PI3K/Akt or Pten pathway, respectively. This result mirrors the growth inhibiting effects of a Mgat5 ablation observed in MEFs.

The presented studies confirm and extend the connection between receptor glycan structure and cell growth as outlined by the Dennis and Demetriou groups in Cell. An exciting potential future direction of this work will be to integrate their findings with cotranslational modifications and regulation of other signaling pathways.

Author: Mirko von Elstermann