Cytosolic O‐glycosylation is abundant in nerve terminals

Cole, Robert N.; Hart, Gerald W.

doi:10.1046/j.1471-4159.2001.00655.x

Cited by 184 publications

(130 citation statements)

References 73 publications

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“…The unfractionated rat brain homogenate contained both of these species, as well as a third major UCH-L1 species, which may be phosphorylated and/or O-glycosylated ( Fig. 1 Biii) (20). These 3 forms of UCH-L1 also were found in cell lysates from human neuroblastoma SH-SY5Y cells (Fig.…”

Section: A Subpopulation Of Uch-l1 (Uch-l1 M ) Is Tightly Bound To Mementioning

confidence: 88%

“…The study reported here was initiated to identify posttranslational modifications of UCH-L1 that distinguish it from its widely expressed homolog UCH-L3 and that may be critical for its in vivo activity. UCH-L1 is O-glycosylated (20) and monoubiquitinated (21). We report here an additional modification that may significantly have an impact on its enzymatic and/or binding activities: UCH-L1 is farnesylated and associated with neuronal membranes, including the endoplasmic reticulum.…”

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confidence: 86%

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Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Liu

Meray

Grammatopoulos³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

127

131

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Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is linked to Parkinson's disease (PD) and memory and is selectively expressed in neurons at high levels. Its expression pattern suggests a function distinct from that of its widely expressed homolog UCH-L3. We report here that, in contrast to UCH-L3, UCH-L1 exists in a membrane-associated form (UCH-L1 M ) in addition to the commonly studied soluble form. C-terminal farnesylation promotes the association of UCH-L1 with cellular membranes, including the endoplasmic reticulum. The amount of UCH-L1 M in transfected cells is shown to correlate with the intracellular level of ␣-synuclein, a protein whose accumulation is associated with neurotoxicity and the development of PD. Reduction of UCH-L1 M in cell culture models of ␣-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces ␣-synuclein levels and increases cell viability. Proteasome function is not affected by UCH-L1 M , suggesting that it may negatively regulate the lysosomal degradation of ␣-synuclein. Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies.farnesylation ͉ synuclein

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Section: A Subpopulation Of Uch-l1 (Uch-l1 M ) Is Tightly Bound To Mementioning

confidence: 88%

mentioning

confidence: 86%

Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Liu

Meray

Grammatopoulos³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

127

131

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“…The association between OGT and PP1 is particularly intriguing, as it may provide a direct mechanism to couple O-GlcNAc glycosylation to dephosphorylation of specific substrates. Although OGT is found in the nucleus, cytosol and mitochondria, it is particularly enriched in the nucleus 15 and the soluble synaptic compartment 16 .…”

Section: The Enzymes Ogt and Ogamentioning

confidence: 99%

“…Like OGT, OGA seems to be highly active at neuronal synapses 16 , and it is also found in the nucleus and cytosol 30 . OGA contains an N-terminal glycosidase domain and a putative Cterminal histone acetyltransferase (HAT) domain 31 .…”

Section: The Enzymes Ogt and Ogamentioning

confidence: 99%

“…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 .…”

Section: Introductionmentioning

confidence: 99%

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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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Hepatocyte nuclear factor 1 alpha (HNF1A) regulates transcription of O‐GlcNAc transferase in a negative feedback mechanism

Zhang

Xie

et al. 2019

FEBS Letters

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O‐GlcNAc transferase (OGT)‐catalyzed protein O‐GlcNAcylation is implicated in diverse cellular events. In the present study, we report the regulation of ogt transcription by the hepatocyte nuclear factor 1 homologue A (HNF1A) in HEK293T cells. We first identified a core ogt promoter (−150 to +200 bp) and confirmed its binding to the transcription factor HNF1A. We found that HNF1A regulates ogt transcription in a time‐dependent manner and that O‐GlcNAcylation of HNF1A represses ogt transcription. Electron‐transfer dissociation based tandem mass spectrometry analysis revealed 14 O‐GlcNAc sites on HNF1A, six of which are predominantly modified, including Ser303/304, Ser471, Ser560 and Thr563/564. We further found that loss of O‐GlcNAcylation at Ser303/304 or Thr563/564 significantly elevates ogt transcription. These findings highlight a negative feedback mechanism for ogt transcription, which partially explains the homeostasis of cellular O‐GlcNAcylation.

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Cytosolic O‐glycosylation is abundant in nerve terminals

Cited by 184 publications

References 73 publications

Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Chemical approaches to understanding O-GlcNAc glycosylation in the brain

Hepatocyte nuclear factor 1 alpha (HNF1A) regulates transcription of O‐GlcNAc transferase in a negative feedback mechanism

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