The Hexosamine Signaling Pathway: Deciphering the "O-GlcNAc Code"

Love, Dona C.; Hanover, John A.

doi:10.1126/stke.3122005re13

Cited by 396 publications

(454 citation statements)

References 169 publications

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“…O‐GlcNAcylation is regulated by OGT and OGA, which are enriched in brain (Kreppel et al ., 1997; Gao et al ., 2001; Okuyama & Marshall, 2003; Love & Hanover, 2005). Mouse brain‐specific deletion of OGT results in perinatal lethality associated with severe motor defects (O'Donnell et al ., 2004).…”

Section: Discussionmentioning

confidence: 99%

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

Xie

Jin

et al. 2016

Aging Cell

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SummaryAlzheimer's disease (AD) is characterized clinically by memory loss and cognitive decline. Protein kinase A (PKA)‐CREB signaling plays a critical role in learning and memory. It is known that glucose uptake and O‐GlcNAcylation are reduced in AD brain. In this study, we found that PKA catalytic subunits (PKAcs) were posttranslationally modified by O‐linked N‐acetylglucosamine (O‐GlcNAc). O‐GlcNAcylation regulated the subcellular location of PKAcα and PKAcβ and enhanced their kinase activity. Upregulation of O‐GlcNAcylation in metabolically active rat brain slices by O‐(2‐acetamido‐2‐deoxy‐d‐glucopyranosylidenamino) N‐phenylcarbamate (PUGNAc), an inhibitor of N‐acetylglucosaminidase, increased the phosphorylation of tau at the PKA site, Ser214, but not at the non‐PKA site, Thr205. In contrast, in rat and mouse brains, downregulation of O‐GlcNAcylation caused decreases in the phosphorylation of CREB at Ser133 and of tau at Ser214, but not at Thr205. Reduction in O‐GlcNAcylation through intracerebroventricular injection of 6‐diazo‐5‐oxo‐l‐norleucine (DON), the inhibitor of glutamine fructose‐6‐phosphate amidotransferase, suppressed PKA‐CREB signaling and impaired learning and memory in mice. These results indicate that in addition to cAMP and phosphorylation, O‐GlcNAcylation is a novel mechanism that regulates PKA‐CREB signaling. Downregulation of O‐GlcNAcylation suppresses PKA‐CREB signaling and consequently causes learning and memory deficits in AD.

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Section: Discussionmentioning

confidence: 99%

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

Xie

Jin

et al. 2016

Aging Cell

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“…Both enzymes are most highly expressed in the brain and exist as several different isoforms 2,22 . Three distinct isoforms of OGT have been identified, including a 110-kDa and a 78-kDa isoform, which can assemble into multimers 23,24 , and a smaller mitochondrial isoform.…”

Section: The Enzymes Ogt and Ogamentioning

confidence: 99%

Chemical approaches to understanding O-GlcNAc glycosylation in the brain

2008

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O -GlcNAc glycosylation is a unique, dynamic form of glycosylation found on intracellular proteins of all multicellular organisms. Studies suggest that O-GlcNAc represents a key regulatory modification in the brain, contributing to transcriptional regulation, neuronal communication and neurodegenerative disease. Recently, several new chemical tools have been developed to detect and study the modification, including chemoenzymatic tagging methods, quantitative proteomics strategies and small-molecule inhibitors of O-GlcNAc enzymes. Here we highlight some of the emerging roles for O-GlcNAc in the nervous system and describe how chemical tools have significantly advanced our understanding of the scope, functional significance and cellular dynamics of this modification.O-GlcNAc glycosylation, the covalent attachment of β-N-acetylglucosamine to serine or threonine residues of proteins, is an unusual form of protein glycosylation 1 (Fig. 1). Unlike other types of glycosylation, this single-sugar modification occurs on intracellular proteins and is not elaborated further into complex glycans. The O-GlcNAc transferase (OGT) enzyme is a soluble protein that is found in the cytosol, nucleus and mitochondria 2 , rather than in the endoplasmic reticulum or Golgi. The dynamics of O-GlcNAc are also unique among sugar modifications, being cycled on a shorter time scale than protein turnover 3 . Thus, in many respects O-GlcNAc is more akin to phosphorylation than to conventional forms of glycosylation. Several reviews have described the roles of O-GlcNAc in cellular processes, such as transcription 2,4 , the stress response 5,6 , apoptosis 7,8 , signal transduction 2,9 , glucose sensing 5,10 and proteasomal degradation 5 . Only a few reviews have highlighted the importance of O-GlcNAc glycosylation in the nervous system, and those reports have focused on its potential impact on neurodegenerative diseases 11,12 . However, several lines of evidence suggest that O-GlcNAc has crucial roles in both neuronal function and dysfunction. The enzymes responsible for the modification are most highly expressed in the brain 13,14 and are enriched at neuronal synapses 15,16 . Neuron-specific deletion of the OGT gene in mice leads to abnormal development and locomotor defects, resulting in neonatal death 17 . The O-GlcNAc modification is abundant in the brain and present on many proteins important for transcription, neuronal signaling and synaptic plasticity, such as cAMPresponsive element binding protein (CREB) 18 , synaptic Ras GTPase-activating protein (synGAP) 19 and β-amyloid precursor protein (APP) 20 . An intriguing interplay between OGlcNAc glycosylation and phosphorylation has been observed in cerebellar neurons, wherein activation of certain kinase pathways reduces O-GlcNAc levels on cytoskeleton-

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“…Furthermore, intracellular UDP-GlcNAc levels fluctuate according to nutrient availability, hence affecting processes like protein O-GlcNAc-ylation and the branching of N-glycans [15]. These dynamic changes themselves influence multiple signaling pathways [16], thereby complicating even further the analysis of the functional impact of GFPT1 mutations.…”

Section: Glutamine-fructose-6-phosphate Transaminasementioning

confidence: 99%

Diseases of glycosylation beyond classical congenital disorders of glycosylation

Hennet

2012

Biochimica et Biophysica Acta (BBA) - General Subjects

116

103

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BACKGROUND: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. SCOPE OF REVIEW: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. MAJOR CONCLUSIONS: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. GENERAL SIGNIFICANCE: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics.

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The Hexosamine Signaling Pathway: Deciphering the "O-GlcNAc Code"

Cited by 396 publications

References 169 publications

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

Chemical approaches to understanding O-GlcNAc glycosylation in the brain

Diseases of glycosylation beyond classical congenital disorders of glycosylation

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