Abstract
O-linked N-acetylglucosamine, better known as O-GlcNAc, is a sugar post-translational modification participating in a diverse range of cell functions. Disruptions in the cycling of O-GlcNAc mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively, is a driving force for aberrant cell signaling in disease pathologies, such as diabetes, obesity, Alzheimer's disease, and cancer. Production of UDP-GlcNAc, the metabolic substrate for OGT, by the Hexosamine Biosynthetic Pathway (HBP) is controlled by the input of amino acids, fats, and nucleic acids, making O-GlcNAc a key nutrient-sensor for fluctuations in these macromolecules. The mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways also participate in nutrient-sensing as a means of controlling cell activity and are significant factors in a variety of pathologies. Research into the individual nutrient-sensitivities of the HBP, AMPK, and mTOR pathways has revealed a complex regulatory dynamic, where their unique responses to macromolecule levels coordinate cell behavior. Importantly, cross-talk between these pathways fine-tunes the cellular response to nutrients. Strong evidence demonstrates that AMPK negatively regulates the mTOR pathway, but O-GlcNAcylation of AMPK lowers enzymatic activity and promotes growth. On the other hand, AMPK can phosphorylate OGT leading to changes in OGT function. Complex sets of interactions between the HBP, AMPK, and mTOR pathways integrate nutritional signals to respond to changes in the environment. In particular, examining these relationships using systems biology approaches might prove a useful method of exploring the complex nature of cell signaling. Overall, understanding the complex interactions of these nutrient pathways will provide novel mechanistic information into how nutrients influence health and disease.
Highlights
At its core, pathology is largely a matter of cell signaling gone awry
In glucose-deprived HepG2 cells, OGA transcription was suppressed and O-GlcNAc transferase (OGT) expression was upregulated coinciding with a dramatic amplification in global O-GlcNAcylation [12] and decreased activity for glycogen synthase (GS), the enzyme responsible for constructing glycogen from individual glucose molecules [12]
A protein complex referred to as the Ragulator must first recruit RAS homolog enriched in brain (Rheb) and mTORC1 to the surface of a lysosome in order for activation of mTORC1 to occur; for cells lacking Ragulator components, mTORC1 activity was undetected, indicating that lysosomal localization was a necessary step in the mammalian target of rapamycin (mTOR) pathway [32]
Summary
Pathology is largely a matter of cell signaling gone awry. Think of it as a game of “Rumors,” where a group of players are passing a message down the line by whispering it to each other, but when it reaches the last person and they announce it, the message is entirely different from the original. A PTM can propagate a signal cascade to change the function of a final target, act as a sensor for regulators of a pathway, or alter the interactions of specific proteins in the pathway. Nutrientsensing is a vital aspect of many different pathways, including the mammalian target of rapamycin (mTOR) and AMP-activated protein kinase pathways (AMPK). By understanding how these pathways react to nutrient levels and how that impacts their interactions between one another, we can begin to ascertain how nutrient sensing impacts overall cell activity [12]. THE HEXOSAMINE BIOSYNTHETIC PATHWAY, mTOR PATHWAY, AND AMPK PATHWAY PARTICIPATE IN NUTRIENT SENSING
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