dbOGAP - An Integrated Bioinformatics Resource for Protein O-GlcNAcylation

Wang, Jinlan; Torii, Manabu; Liu, Hongfang; Hart, Gerald W.; Hu, Zhang

doi:10.1186/1471-2105-12-91

Cited by 98 publications

(111 citation statements)

References 41 publications

(52 reference statements)

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“…2A). Interestingly, similar sequence preference has been observed from O-GlcNAcylation sites identified in animals (11,12,24,25), suggesting that the plant and animal OGTs have consistent enzymatic preferences.…”

Section: Enrichment and Identification Of Glcnacylated And Phosphorylmentioning

confidence: 61%

“…YTH proteins bind to m(6)A-containing mRNA and regulate messenger RNA stability (39). They have been shown to be modified by O-GlcNAcylation in murine synapse and human tissues (25). We generated transgenic Arabidopsis overexpressing a YFP-ECT7 fusion protein and performed two replicates of immunoprecipitation, followed by mass spectrometry.…”

Section: O-glcnac Modification Of Proteins Involved In Transcriptionmentioning

confidence: 99%

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Proteomic analysis reveals O-GlcNAc modification on proteins with key regulatory functions in Arabidopsis

Chalkley

Maynard

et al. 2017

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

107

161

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Genetic studies have shown essential functions of O-linked N-acetylglucosamine (O-GlcNAc) modification in plants. However, the proteins and sites subject to this posttranslational modification are largely unknown. Here, we report a large-scale proteomic identification of O-GlcNAc-modified proteins and sites in the model plant Arabidopsis thaliana. Using lectin weak affinity chromatography to enrich modified peptides, followed by mass spectrometry, we identified 971 O-GlcNAc-modified peptides belonging to 262 proteins. The modified proteins are involved in cellular regulatory processes, including transcription, translation, epigenetic gene regulation, and signal transduction. Many proteins have functions in developmental and physiological processes specific to plants, such as hormone responses and flower development. Mass spectrometric analysis of phosphopeptides from the same samples showed that a large number of peptides could be modified by either O-GlcNAcylation or phosphorylation, but cooccurrence of the two modifications in the same peptide molecule was rare. Our study generates a snapshot of the O-GlcNAc modification landscape in plants, indicating functions in many cellular regulation pathways and providing a powerful resource for further dissecting these functions at the molecular level.of proteins consisting of a single O-linked N-acetylglucosamine attached to serine and threonine residues. It has been extensively studied in animals, where it regulates a wide range of developmental and metabolic processes. O-GlcNAcylation is dynamically controlled by two enzymes: an O-GlcNAc transferase (OGT) and an O-GlcNAcase (OGA), which add and remove O-GlcNAc, respectively. O-GlcNAcylation occurs in the cytoplasm, nucleus, and mitochondria and has been implicated in cellular processes, including transcription, translation, signal transduction, nuclear pore function, epigenetic regulation and proteasomal degradation (1). Altered levels of protein O-GlcNAcylation in animals have been associated with neurodegeneration, diabetes, cardiovascular diseases, and cancer (2) whereas knock out of OGT is embryonically lethal (3).The model plant Arabidopsis has two putative OGTs: SPINDLY (SPY) and SECRET AGENT (SEC). The spy mutant was identified based on its phenotypes that mimic gibberellin-treated plants, with elongated stems (4). The spy plants also show defects in light and cytokinin responses, leaf morphology and phyllotaxy, root growth, meristem activity, and circadian rhythms (5). The sec mutant displays defects in flower development (6). Although OGT enzymatic activity has been demonstrated in SEC, similar activity in SPY has not been confirmed (7). However, the spy;sec double mutants show severe defects in the development of gametes and are embryonically lethal (7), similar to the OGT knockout mutant in animals. Thus, genetic evidence indicates that O-GlcNAc modification is as important in plants as in animals. But little is known about its specific functions because few O-GlcNAc-modified proteins have been identified...

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Section: Enrichment and Identification Of Glcnacylated And Phosphorylmentioning

confidence: 61%

Section: O-glcnac Modification Of Proteins Involved In Transcriptionmentioning

confidence: 99%

Proteomic analysis reveals O-GlcNAc modification on proteins with key regulatory functions in Arabidopsis

Chalkley

Maynard

et al. 2017

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

107

161

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“…To determine a functional link between placental OGT and transmission of information important in programming changes in the brain, we examined placental gene expression and chromatin regulation patterns, as well as the adult phenotype of placental-specific OGT knockout mice for predictive validity of this EPS biomarker. OGT broadly affects cellular functioning through the unique posttranslational modification, O-GlcNAc, on serine and threonine residues of over 1,000 different intracellular proteins (11). Many of these protein targets (notably RNA polymerase II, histone deacetylase-2, Tet proteins, and core histone H2B) are part of chromatin structure or directly regulate chromatin confirmation (12)(13)(14)(15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction

Howerton

Bale

2014

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

137

130

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Maternal stress is a key risk factor in neurodevelopmental disorders, which often have a sex bias in severity and prevalence. We previously identified O-GlcNAc transferase (OGT) as a placental biomarker in our mouse model of early prenatal stress (EPS), where OGT levels were lower in male compared with female tissue and were further decreased following maternal stress. However, the function of placental OGT in programming the developing brain has not been determined. Therefore, we generated a transgenic mouse with targeted placental disruption of Ogt (Pl-OGT) and examined offspring for recapitulation of the adult EPS phenotype. Pl-OGT hemizygous and EPS male placentas showed similar robust changes in gene expression patterns suggestive of an altered ability to respond to endocrine and inflammatory signals, supporting placental OGT as an important mediator of EPS effects. ChIP-Seq for the O-GlcNAc mark identified the 17 beta hydroxysteroid dehydrogenase-3 (Hsd17b3) locus in male EPS placentas, which correlated with a reduction in Hsd17b3 expression and concordant reduced testosterone conversion. Remarkably, Pl-OGT adult offspring had reduced body weights and elevated hypothalamic-pituitary-adrenal stress axis responsivity, recapitulating phenotypes previously reported for EPS males. Further, hypothalamic microarray gene-set enrichment analyses identified reduced mitochondrial function in both Pl-OGT and EPS males. Cytochrome c oxidase activity assays verified this finding, linking reduced placental OGT with critical brain programming. Together, these studies confirm OGT as in important placental biomarker of maternal stress and demonstrate the profound impact a single placental gene has on longterm metabolic and neurodevelopmental programming that may be related to an increased risk for neurodevelopmental disorders.M aternal stress early in gestation has been identified as a risk factor for neurodevelopmental disorders, including autism spectrum disorders and schizophrenia. Despite strong epidemiological evidence, there remains a lack of specific mechanisms of disease development or predictive biomarkers of disease risk. Examination of the placenta is a promising avenue to find these mechanisms and biomarkers because of features of its biology and accessibility for diagnostic purposes postparturition. The placenta is uniquely positioned at the interface between the maternal and fetal compartments and is rapidly developing during the period of gestation at which maternal stress has been identified to increase disease risk to the offspring (1-5). We previously identified a reduction in O-GlcNAc transferase (OGT), an important O-glycotransferase enzyme that plays a critical role in regulation of gene expression through chromatin remodeling, in male placentas following early prenatal stress (EPS) (4). Placental OGT is basally lower in males due to its X-linkage and escaping of X-inactivation in the placenta and further reduced in our mouse model of EPS. Additionally, we established that a targeted reduction of placen...

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“…O-GlcNAc-modified proteins are involved in many cellular processes including the cellular stress response. HK hexokinase, G6P-I glucose 6-phosphate isomerase, Glc glucose, NAc N-acetyl developed a neural network for predicting O-GlcNAc modification sites (Wang et al 2011). The activity of OGT appears to be regulated by substrate targeting (discussed above), the levels of UDP and UDPGlcNAc, and potentially by other post-translational modifications.…”

Section: O-glcnac Transferasementioning

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

116

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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dbOGAP - An Integrated Bioinformatics Resource for Protein O-GlcNAcylation

Cited by 98 publications

References 41 publications

Proteomic analysis reveals O-GlcNAc modification on proteins with key regulatory functions in Arabidopsis

Proteomic analysis reveals O-GlcNAc modification on proteins with key regulatory functions in Arabidopsis

Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction

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

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