The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine

Abstract

The enzymes of O-GlcNAc cycling couple the nutrient-dependent synthesis of UDP-GlcNAc to OGlcNAc modification of Ser/Thr residues of key nuclear and cytoplasmic targets. This series of reactions culminating in O-GlcNAcylation of targets has been termed the Hexosamine Signaling Pathway (HSP). The evolutionarily ancient enzymes of O-GlcNAc cycling have co-evolved with other signaling effecter molecules; they are recruited to their targets by many of the same mechanisms used to organize canonic kinase-dependent signaling pathways. This co-recruitment of the enzymes of O-GlcNAc cycling drives a binary switch impacting pathways of anabolism and growth (nutrient uptake) and catabolic pathways (nutrient sparing and salvage). The Hexosamine Signaling Pathway (HSP) has thus emerged as a versatile cellular regulator modulating numerous cellular signaling cascades influencing growth, metabolism, cellular stress, circadian rhythm, and host-pathogen interactions. In mammals, the nutrient-sensing HSP has been harnessed to regulate such cell-specific functions as neutrophil migration, and activation of B-cells and T-cells. This review summarizes the diverse approaches being used to examine O-GlcNAc cycling. It will emphasize the impact OGlcNAcylation has upon signaling pathways that may be become deregulated in diseases of the immune system, diabetes mellitus, cancer, cardiovascular disease, and neurodegenerative diseases.

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

“…We also tested whether glucose metabolism contributes to the regulation of OGT. Alterations in cell metabolism may indirectly influence OGT activity by affecting the availability of UDP-GlcNAc, which serves as the nucleotide sugar donor for OGT (26)(27)(28). After activation, T cells exhibit a dramatic increase in the consumption of glucose and glutamine (75).…”

“…In addition to direct regulation of its localization or expression, OGT activity may also be regulated indirectly by the availability of its nucleotide sugar donor substrate, UDP-GlcNAc, which, in turn, is heavily influenced by cell metabolism (26)(27)(28). In response to activation, T cells exhibit a remarkable metabolic shift from fatty acid oxidation to glycolysis (50)(51)(52).…”

“…Furthermore, conditional deletion of OGT results in cellular senescence and apoptosis in numerous cell types, including T cells (25). Considering that abnormal O-GlcNAc levels, possibly stemming from alterations in metabolism (26)(27)(28)(29), may contribute to the pathology of several diseases, including cancer, diabetes, and neurodegeneration (29)(30)(31)(32)(33)(34)(35)(36), a greater understanding of O-GlcNAc biology in T cells could help to explain the impact of metabolic health on the function of the immune system.making the relevance to primary T cells unclear. Furthermore, only a selected few proteins were surveyed.…”

Metabolic cross-talk allows labeling of O-linked β- N -acetylglucosamine-modified proteins via the N -acetylgalactosamine salvage pathway

“…Specifically, N-acetylglucosamine (GlcNAc) is reversibly attached to serine and threonine side chains of numerous intracellular proteins to regulate their function, localization, and stability ( Fig. 1A) (1,2). In mammals, the resulting O-linked β-GlcNAc modification (O-GlcNAc) controls diverse aspects of cell physiology in a range of tissue types, and dysregulation of O-GlcNAc signaling is implicated in such human diseases as type II diabetes and neurodegeneration (3,4).…”

Metabolic Signature Genes Associated with Susceptibility to Pyruvate Kinase, Muscle Type 2 Gene Ablation in Cancer Cells

“…In addition, all the sensitive cells and the SNU-449 cells commonly expressed a high level of GFPT2, a catalytic enzyme in the hexosamine biosynthetic pathway, an arm of glucose metabolism that generates UDP-N-acetyl-d-glucosamine (UDP-GlcNAc), a donor substrate for glycosylation reactions (Figs. 4A and 4B) (Hanover et al, 2010). A recent study showed that glucose availability modulated cel-lular uptake of glutamine through the hexosamine biosynthetic pathway (Wellen et al, 2010 Table 5).…”