O-GlcNAc Modification Is an Endogenous Inhibitor of the Proteasome

Zhang, Fengxue; Su, Kaihong; Yang, Xiaoyong; Bowe, Damon B.; Paterson, Andrew J.; Kudlow, Jeffrey E.

doi:10.1016/s0092-8674(03)00974-7

Cited by 384 publications

(349 citation statements)

References 49 publications

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“…Synthetic histone peptides (1pmol/ul) were infused at a flow rate of 60 nl/min into a ThermoElectron LTQ ion trap mass spectrometer modified to perform ETD. (A) The CAD spectrum from histone H3 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), TAR(acK) STGGKAPRKQL, is illustrated. The spectrum consists of a product ion corresponding to the neutral loss of water with minimal peptide backbone fragmentation.…”

Section: Abbreviations Usedmentioning

confidence: 99%

“…For example, posttranslational modifications (PTM) such as phosphorylation, acetylation, and methylation are used as chemical switches to activate/inactive the histone regulation of gene transcription, DNA replication, and DNA damage repair [4]. In the ubiquitin-proteasome pathway, phosphorylation [5,6] and O-linked N-acetylglucosamine (O-GlcNAc) modifications [7,8] play a major role in the degradation process of intracellular proteins. Tyrosine sulfonation has been implicated in the mediation of inflammation, leukocyte adhesion, chemokine receptor signaling, and modulation of the blood coagulation cascade.…”

Section: Introductionmentioning

confidence: 99%

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The utility of ETD mass spectrometry in proteomic analysis

Mikesh

Ueberheide

Chen

et al. 2006

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

496

490

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Mass spectrometry has played an integral role in the identification of proteins and their posttranslational modifications (PTM). However, analysis of some PTMs, such as phosphorylation, sulfonation, and glycosylation, is difficult with collision-activated dissociation (CAD) since the modification is labile and preferentially lost over peptide backbone fragmentation, resulting in little to no peptide sequence information. The presence of multiple basic residues also makes peptides exceptionally difficult to sequence by conventional CAD mass spectrometry. Here we review the utility of electron transfer dissociation (ETD) mass spectrometry for sequence analysis of posttranslationally modified and/or highly basic peptides. Phosphorylated, sulfonated, glycosylated, nitrosylated, disulfide bonded, methylated, acetylated, and highly basic peptides have been analyzed by CAD and ETD mass spectrometry. CAD fragmentation typically produced spectra showing limited peptide backbone fragmentation. However, when these peptides were fragmented using ETD, peptide backbone fragmentation produced a complete or almost complete series of ions and thus extensive peptide sequence information. In addition, labile PTMs remained intact. These examples illustrate the utility of ETD as an advantageous tool in proteomic research by readily identifying peptides resistant to analysis by CAD. A further benefit is the ability to analyze larger, non-tryptic peptides, allowing for the detection of multiple PTMs within the context of one another.

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Section: Abbreviations Usedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The utility of ETD mass spectrometry in proteomic analysis

Mikesh

Ueberheide

Chen

et al. 2006

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

496

490

View full text Add to dashboard Cite

show abstract

“…Secondly, as discussed below, data suggests that OGlcNAc may regulate ubiquitination. Thirdly, O-GlcNAc is implicated in regulating the proteasome directly, as highlighted by studies showing that that numerous proteins in the proteasome are O-GlcNAc-modified and that enhanced OGlcNAcylation may inhibit proteasome function (Zhang et al 2003;Sumegi et al 2003).…”

Section: Other Ptm Rolesmentioning

confidence: 99%

“…O-GlcNAc is thought to regulate these proteins in a manner analogous to protein phosphorylation. O-GlcNAc has been demonstrated to alter numerous protein functions that include: DNA binding and transactivation (Jackson and Tjian 1989;Ozcan et al 2010;Comer and Hart 1999;Gao et al 2003;Sayat et al 2008), protein-protein interactions (Lim and Chang 2010;Ise et al 2010;Guinez et al 2010;Guinez et al 2007;Guinez et al 2006), protein degradation (Cheng and Hart 2001;Han and Kudlow 1997;Zhang et al 2003), protein and enzyme activity Rengifo et al 2007;Zhang et al 2003;Dias et al 2009;Bimboese et al 2011), and protein localization (Sayat et al 2008;Dudognon et al 2004) among many others .…”

mentioning

confidence: 99%

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

Groves

Lee

Yildirir

et al. 2013

Cell Stress and Chaperones

120

112

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O-linked N-acetyl-β-D-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (OGlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced OGlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer's and Parkinson's diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.

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“…In an animal model of ALS, the O-GlcNAc levels of neurofilament protein M are decreased at the same time as its phosphorylation levels are increased 61 . Finally, O-GlcNAc glycosylation has been demonstrated to inhibit the proteasome 69 , thus providing a mechanism to couple ubiquitin-mediated protein degradation to the general metabolic state of the cell. Blocking the removal of O-GlcNAc from the proteasome leads to increased protein ubiquitination 69 and possibly neuronal apoptosis 70 .…”

Section: Neurodegenerative Diseasementioning

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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O-GlcNAc Modification Is an Endogenous Inhibitor of the Proteasome

Cited by 384 publications

References 49 publications

The utility of ETD mass spectrometry in proteomic analysis

The utility of ETD mass spectrometry in proteomic analysis

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

Chemical approaches to understanding O-GlcNAc glycosylation in the brain

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