Hexosamine pathway and (ER) protein quality control

Denzel, Martin S.; Antebi, Adam

doi:10.1016/j.ceb.2014.10.001

Cited by 59 publications

(55 citation statements)

References 41 publications

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“…Finally, proteins can be modified by glycosylations. There are N‐linked and O‐linked glycosylations, as well as O‐GlcNAcylation (Denzel and Antebi ). All glycosylations involve the hexosamine pathway, and its product UDP‐GlcNAc (Denzel and Antebi ).…”

Section: Regulation Of Metabolism By Ptmsmentioning

confidence: 99%

Metabolic control of signalling pathways and metabolic auto‐regulation

Lorendeau

Christen

Rinaldi

et al. 2015

Biology of the Cell

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Metabolic alterations have emerged as an important hallmark in the development of various diseases. Thus, understanding the complex interplay of metabolism with other cellular processes such as cell signalling is critical to rationally control and modulate cellular physiology. Here, we review in the context of mammalian target of rapamycin, AMP-activated protein kinase and p53, the orchestrated interplay between metabolism and cellular signalling as well as transcriptional regulation. Moreover, we discuss recent discoveries in auto-regulation of metabolism (i.e. how metabolic parameters such as metabolite levels activate or inhibit enzymes and thus metabolic pathways). Finally, we review functional consequences of post-translational modification on metabolic enzyme abundance and/or activities.

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Section: Regulation Of Metabolism By Ptmsmentioning

confidence: 99%

Metabolic control of signalling pathways and metabolic auto‐regulation

Lorendeau

Christen

Rinaldi

et al. 2015

Biology of the Cell

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“…The hexosamine biosynthetic pathway (HBP) plays a central role in sensing the nutritional status of the cell, since it integrates molecules coming from carbohydrates, fatty acids, amino acids and nucleotides metabolism3. The HBP converts fructose-6-phosphate, a glucose derivative, into UDP-N-acetylglucosamine (UDP-GlcNAc), a central nucleotide sugar acting as a donor substrate for the glycosylation of proteins and lipids.…”

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confidence: 99%

Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway

Chaveroux

Sarcinelli

Barbet

et al. 2016

Sci Rep

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The hexosamine biosynthetic pathway (HBP) is a nutrient-sensing metabolic pathway that produces the activated amino sugar UDP-N-acetylglucosamine, a critical substrate for protein glycosylation. Despite its biological significance, little is known about the regulation of HBP flux during nutrient limitation. Here, we report that amino acid or glucose shortage increase GFAT1 production, the first and rate-limiting enzyme of the HBP. GFAT1 is a transcriptional target of the activating transcription factor 4 (ATF4) induced by the GCN2-eIF2α signalling pathway. The increased production of GFAT1 stimulates HBP flux and results in an increase in O-linked β-N-acetylglucosamine protein modifications. Taken together, these findings demonstrate that ATF4 provides a link between nutritional stress and the HBP for the regulation of the O-GlcNAcylation-dependent cellular signalling.The regulation of metabolic fluxes is a key process in the cellular response to changes in nutrient availability, and dysregulation of this process may contribute to the development of various diseases 1,2 . The hexosamine biosynthetic pathway (HBP) plays a central role in sensing the nutritional status of the cell, since it integrates molecules coming from carbohydrates, fatty acids, amino acids and nucleotides metabolism 3 . The HBP converts fructose-6-phosphate, a glucose derivative, into UDP-N-acetylglucosamine (UDP-GlcNAc), a central nucleotide sugar acting as a donor substrate for the glycosylation of proteins and lipids. In addition, UDP-GlcNAc is used for the O-GlcNAcylation of proteins, i.e. the addition of N-acetylglucosamine to their serine and threonine residues. Similarly to phosphorylation, O-GlcNAcylation regulates cellular activities, such as signalling and transcription 4 . It has been proposed that O-GlcNAcylated proteins modulate cellular responses to nutrient deprivation and stress, and that their dysregulation is implicated in a wide range of pathologies 5 . Despite these wide-ranging biological effects, the mechanisms underlying the adaptation of the HBP flux to nutrient availability remains poorly understood.The first and rate-limiting enzyme of the HBP, namely glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1), which drives the HBP flux, is involved in various physiopathological processes 6-9 . GFAT1 activity is inhibited by UDP-GlcNAc, the end product of the HBP 10 , and the AMP-activated protein kinase-mediated phosphorylation 11 . In contrary, GFAT1 is stimulated upon phosphorylation by protein kinase A and calcium/ calmodulin-dependent protein kinase II 12 . More recently, it was shown that GFAT1 production is upregulated by a transcription factor of the unfolded protein response (UPR), namely the spliced form of X-box binding protein 1 (XBP1s), resulting in the stimulation of the HBP flux and protein O-GlcNAcylation 13 . These authors unveiled in this way an intrinsic link between the HBP and disruption of the endoplasmic reticulum (ER) homeostasis, i.e. ER stress, which activates the UPR.UPR signalling is mediat...

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“…In this context, the ability of HBP to integrate and sense the main intracellular metabolites strongly supports the important role of this pathway and its final product, UDP‐Glc N Ac, in the regulation of cell metabolism both in physiological conditions and in the metabolic changes observed in several human diseases, such as cancer . Furthermore, HBP plays a central role in sensing the nutritional status of the tumor cell, because it integrates molecules from carbohydrates, fatty acids, amino acids, and nucleotides metabolism . The enhanced uptake and utilization of glucose and glutamine, as well as the increased fatty acid uptake and biosynthesis, at least in the specific context and tumor stage, may provide an explanation for the enhanced HBP flux observed in tumors …”

Section: The Hexosamine Biosynthetic Pathway In Kras‐mutant Crcmentioning

confidence: 71%

“…77 Furthermore, HBP plays a central role in sensing the nutritional status of the tumor cell, because it integrates molecules from carbohydrates, fatty acids, amino acids, and nucleotides metabolism. 78 The enhanced uptake and utilization of glucose and glutamine, as well as the increased fatty acid uptake and biosynthesis, at least in the specific context and tumor stage, 79 may provide an explanation for the enhanced HBP flux observed in tumors. 80,81 Despite these wide-ranging biological effects, the mechanisms underlying the adaptation of the HBP flux in KRAS-mutant CRC cell availability remains poorly understood.…”

Section: The Hexosamine Biosynthetic Pathway In Kras-mutant Crcmentioning

confidence: 99%

Strategies for targeting energy metabolism in Kirsten rat sarcoma viral oncogene homolog ‐mutant colorectal cancer

Wang

Yin

et al. 2018

J of Cellular Biochemistry

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Alterations in cellular energy metabolism play critical roles in colorectal cancer (CRC). These alterations, which correlate to KRAS mutations, have been identified as energy metabolism signatures. This review summarizes the relationship between colorectal tumors associated with mutated KRAS and energy metabolism, especially for the deregulated energy metabolism that affects tumor cell proliferation, invasion, and migration. Furthermore, this review will concentrate on the role of metabolic genes, factors and signaling pathways, which are coupled with the primary energy source connected with the KRAS mutation that induces metabolic alterations. Strategies for targeting energy metabolism in mutated KRAS CRC are also introduced. In conclusion, deregulated energy metabolism has a close relationship with KRAS mutations in colorectal tumors. Therefore, selective inhibitors, agents against metabolic targets or KRAS signaling, may be clinically useful for colorectal tumor treatment through a patient‐personalized approach.

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Hexosamine pathway and (ER) protein quality control

Cited by 59 publications

References 41 publications

Metabolic control of signalling pathways and metabolic auto‐regulation

Metabolic control of signalling pathways and metabolic auto‐regulation

Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway

Strategies for targeting energy metabolism in Kirsten rat sarcoma viral oncogene homolog ‐mutant colorectal cancer

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