An Overview of Glycosylation and its Impact on Cardiovascular Health and Disease

Loaeza-Reyes, Karen Julissa; Zenteno, Edgar; Moreno-Rodríguez, Adriana; Torres‐Rosas, Rafael; Argueta-Figueroa, Liliana; Salinas-Marín, Roberta; Castillo-Real, Lizet Monserrat; Pina-Canseco, Socorro; Cervera, Yobana Pérez

doi:10.3389/fmolb.2021.751637

Cited by 39 publications

(29 citation statements)

References 241 publications

(278 reference statements)

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“…Mutations in PMM2 cause a congenital disorder of glycosylation 61 with neurological and cardiac manifestations 62 . Glycosylation has been linked to cardiovascular 63 and neuroinflammatory 64 diseases, as well as schizophrenia 65 . In sum, HAND1::TCF3 target genes with neural-cardiac roles provide a means to elucidate genetic causes of comorbidity between schizophrenia and cardiovascular diseases 66 .…”

Section: Resultsmentioning

confidence: 99%

Genetic effects of sequence-conserved enhancer-like elements on human complex traits

Zhu

Wong

2022

Preprint

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Non-coding sequences that are evolutionarily conserved and bio-chemically active offer clues to mechanistic interpretations of human genome-wide association studies (GWAS). However, their genetic effects have not been systematically examined across a wide range of human tissues and traits. Here we develop a simple method to identify functional elements exhibiting high levels of human-mouse sequence conservation and enhancer-like biochemical activity, which scales well to 313 epigenomic datasets across 106 tissues and cell types. Combining these elements with 468 GWAS of European (EUR) and East Asian (EAS) ancestries, we identify tissue-specific enrichments of heritability and causal variants for many traits, as well as candidate genes that are functionally relevant to body mass index (BMI) and schizophrenia but were not reported in previous GWAS. Our findings provide a comprehensive assessment of how sequence-conserved enhancer-like elements affect complex traits, and reinforce the importance of integrating evolutionary and biochemical data to elucidate human disease genetics.

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Section: Resultsmentioning

confidence: 99%

Genetic effects of sequence-conserved enhancer-like elements on human complex traits

Zhu

Wong

2022

Preprint

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“…It has to be stressed that, O-glycosylation is mainly related to cell processes other than trafficking. This PTM was described in glycocalyx formation, host-microbes interaction, protection from proteolytic cleavage 36 and in several pathological conditions, including cancer 37 , and cardiovascular disease 38 .…”

Section: Discussionmentioning

confidence: 97%

N-glycosylation is crucial for trafficking and stability of SLC3A2 (CD98)

Console

Scalise

Salerno

et al. 2022

Sci Rep

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The type II glycoprotein CD98 (SLC3A2) is a membrane protein with pleiotropic roles in cells, ranging from modulation of inflammatory processes, host–pathogen interactions to association with membrane transporters of the SLC7 family. The recent resolution of CD98 structure in complex with LAT1 showed that four Asn residues, N365, N381, N424, N506, harbour N-glycosylation moieties. Then, the role of N-glycosylation on CD98 trafficking and stability was investigated by combining bioinformatics, site-directed mutagenesis and cell biology approach. Single, double, triple and quadruple mutants of the four Asn exhibited altered electrophoretic mobility, with apparent molecular masses from 95 to 70 kDa. The quadruple mutant displayed a single band of 70 kDa corresponding to the unglycosylated protein. The presence in the membrane and the trafficking of CD98 were evaluated by a biotinylation assay and a brefeldin assay, respectively. Taken together, the results highlighted that the quadruple mutation severely impaired both the stability and the trafficking of CD98 to the plasma membrane. The decreased presence of CD98 at the plasma membrane, correlated with a lower presence of LAT1 (SLC7A5) and its transport activity. This finding opens new perspectives for human therapy. Indeed, the inhibition of CD98 trafficking would act synergistically with LAT1 inhibitors that are under clinical trial for anticancer therapy.

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“…[56][57][58] Emerging evidence indicates that increased HBP flux and accordingly elevated protein O-GlcNAcylation levels lead to endothelial dysfunction in the development of diabetic vasculopathies [59,60] and cardiovascular diseases. [61,62] Nevertheless, the mechanisms regulating tumor UM-UC-3-WT, UM-UC-3-GFKO, and UM-UC-3-OEGF were subcutaneously injected into the right thigh root of 6-week-old female BALB/c nude mice to establish CDX mouse models for BCa, as indicated, followed by administration of sEVs UM-UC-3-OEGF (50 μg/3 days), OSMI-1 (1 mg/kg/2 days), thiamet G (20 mg kg −1 day −1 ), or DON (1 mg kg −1 day −1 ) for 3 weeks. ND represents mice were offered a normal diet.…”

Section: Discussionmentioning

confidence: 99%

“…[ 56 , 57 , 58 ] Emerging evidence indicates that increased HBP flux and accordingly elevated protein O‐GlcNAcylation levels lead to endothelial dysfunction in the development of diabetic vasculopathies [ 59 , 60 ] and cardiovascular diseases. [ 61 , 62 ] Nevertheless, the mechanisms regulating tumor angiogenesis under metabolic stress conditions through HBP‐fuelled O‐GlcNAcylation are poorly understood. It remains unclear whether and how the TME remodels the HBP‐related metabolic process in ECs.…”

Section: Discussionmentioning

confidence: 99%

Bladder Cancer‐Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP‐Related Metabolic Reprogramming and SerRS O‐GlcNAcylation in Endothelial Cells

Peng

Zhang

et al. 2022

Advanced Science

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A malformed tumour vascular network provokes the nutrient-deprived tumour microenvironment (TME), which conversely activates endothelial cell (EC) functions and stimulates neovascularization. Emerging evidence suggests that the flexible metabolic adaptability of tumour cells helps to establish a metabolic symbiosis among various cell subpopulations in the fluctuating TME. In this study, the authors propose a novel metabolic link between bladder cancer (BCa) cells and ECs in the nutrient-scarce TME, in which BCa-secreted glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1) via small extracellular vesicles (sEVs) reprograms glucose metabolism by increasing hexosamine biosynthesis pathway flux in ECs and thus enhances O-GlcNAcylation. Moreover, seryl-tRNA synthetase (SerRS) O-GlcNAcylation at serine 101 in ECs promotes its degradation by ubiquitination and impeded importin 𝜶5-mediated nuclear translocation. Intranuclear SerRS attenuates vascular endothelial growth factor transcription by competitively binding to the GC-rich region of the proximal promotor. Additionally, GFAT1 knockout in tumour cells blocks SerRS O-GlcNAcylation in ECs and attenuates angiogenesis both in vitro and in vivo. However, administration of GFAT1-overexpressing BCa cells-derived sEVs increase the angiogenetic activity in the ECs of GFAT1-knockout mice. In summary, this study suggests that inhibiting sEV-mediated GFAT1 secretion from BCa cells and targeting SerRS O-GlcNAcylation in ECs may serve as novel strategies for BCa antiangiogenetic therapy.

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An Overview of Glycosylation and its Impact on Cardiovascular Health and Disease

Cited by 39 publications

References 241 publications

Genetic effects of sequence-conserved enhancer-like elements on human complex traits

Genetic effects of sequence-conserved enhancer-like elements on human complex traits

N-glycosylation is crucial for trafficking and stability of SLC3A2 (CD98)

Bladder Cancer‐Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP‐Related Metabolic Reprogramming and SerRS O‐GlcNAcylation in Endothelial Cells

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