Glycosphingolipid metabolism in cell fate specification

Russo, Domenico; Capolupo, Laura; Loomba, Jaipreet Singh; Sticco, Lucia; D’Angelo, Giovanni

doi:10.1242/jcs.219204

Cited by 70 publications

(54 citation statements)

References 120 publications

(173 reference statements)

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“…Glycosphingolipids (GSL) consist of a ceramide backbone with a glycan moiety, which can be grouped into a galactosylated (LacCer) or glucosylated ceramide (GlcCer, CerG). This diversity of GSLs is well studied during embryogenesis and at specific developmental stages [ 30 ]. A dramatic change in the GSL composition in mouse lungs is observed between pnd1 and pnd7 [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Hyperoxic Exposure Caused Lung Lipid Compositional Changes in Neonatal Mice

Peterson

Carr

et al. 2020

Metabolites

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Treatments with supplemental oxygen in premature infants can impair lung development, leading to bronchopulmonary dysplasia (BPD). Although a stage-specific alteration of lung lipidome occurs during postnatal lung development, whether neonatal hyperoxia, a known mediator of BPD in rodent models, changes lipid profiles in mouse lungs is still to be elucidated. To answer this question, newborn mice were exposed to hyperoxia for 3 days and allowed to recover in normoxia until postnatal day (pnd) 7 and pnd14, time-points spanning the peak stage of alveologenesis. A total of 2263 lung lipid species were detected by liquid chromatography–mass spectrometry, covering 5 lipid categories and 18 lipid subclasses. The most commonly identified lipid species were glycerophospholipids, followed by sphingolipids and glycerolipids. In normoxic conditions, certain glycerophospholipid and glycerolipid species augmented at pnd14 compared to pnd7. At pnd7, hyperoxia generally increased glycerophospholipid, sphingolipid, and glycerolipid species. Hyperoxia increased NADPH, acetyl CoA, and citrate acid but reduced carnitine and acyl carnitine. Hyperoxia increased oxidized glutathione but reduced catalase. These changes were not apparent at pnd14. Hyperoxia reduced docosahexaenoic acid and arachidonic acid at pnd14 but not at pnd7. Altogether, the lung lipidome changes throughout alveolarization. Neonatal hyperoxia alters the lung lipidome, which may contribute to alveolar simplification and dysregulated vascular development.

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Section: Discussionmentioning

confidence: 99%

Hyperoxic Exposure Caused Lung Lipid Compositional Changes in Neonatal Mice

Peterson

Carr

et al. 2020

Metabolites

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“…Within the lipid raft, receptors, cell adhesion molecules and ligands exist in a dynamic fashion [23]. The balance of biosynthetic and degradation pathways changes upon ageing, affecting levels and distributions of GSLs and their role during development, differentiation and in cancer [1].…”

Section: Functions Of Glycosphingolipidsmentioning

confidence: 99%

“…Glyceroglycolipids are infrequently found in humans, but are ubiquitous throughout plant cells. In contrast, GSLs are highly expressed throughout the central nervous system (CNS) of vertebrates [1,2]. In the brain and spinal cord of vertebrates, GSLs primarily populate lipid rafts within the plasma membrane along with cholesterol and proteins such as receptors, signaling molecules and glycosylphosphatidylinositol (GPI)-anchored proteins.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

Ryckman

Brockhausen

Walia

2020

IJMS

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Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone and a carbohydrate-rich head group. GSLs populate lipid rafts of the cell membrane of eukaryotic cells, and serve important cellular functions including control of cell–cell signaling, signal transduction and cell recognition. Of the hundreds of unique GSL structures, anionic gangliosides are the most heavily implicated in the pathogenesis of lysosomal storage diseases (LSDs) such as Tay-Sachs and Sandhoff disease. Each LSD is characterized by the accumulation of GSLs in the lysosomes of neurons, which negatively interact with other intracellular molecules to culminate in cell death. In this review, we summarize the biosynthesis and degradation pathways of GSLs, discuss how aberrant GSL metabolism contributes to key features of LSD pathophysiology, draw parallels between LSDs and neurodegenerative proteinopathies such as Alzheimer’s and Parkinson’s disease and lastly, discuss possible therapies for patients.

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“…Ceramide glycosylation generates glycosphingolipids (GSLs) and modulates cell processes in response to environmental stress, including assault by various anticancer drugs. Glucosylceramide synthase (GCS) is a rate‐limiting enzyme in GSL synthesis, catalyzing ceramide (Cer) glycosylation that converts Cer into glucosylceramide (GlcCer) at the cis ‐membrane of Golgi apparatus, thereby providing GlcCer as a precursor for various GlcCer‐based GSLs 1,2 . GlcCer is further converted to lactosylceramide (LacCer), which is the biosynthetic branching point for the formation of major GSLs, including globo‐series (globotriaosylceramide Gb3, globopentaosylceramide Gb5, etc.)…”

Section: Introductionmentioning

confidence: 99%

Gb3‐cSrc complex in glycosphingolipid‐enriched microdomains contributes to the expression of p53 mutant protein and cancer drug resistance via β‐catenin–activated RNA methylation

et al. 2020

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Glucosylceramide synthase (GCS) is a key enzyme catalyzing ceramide glycosylation to generate glucosylceramide (GlcCer), which in turn serves as the precursor for cells to produce glycosphingolipids (GSLs). In cell membranes, GSLs serve as essential components of GSL‐enriched microdomains (GEMs) and mediate membrane functions and cell behaviors. Previous studies showed that ceramide glycosylation correlates with upregulated expression of p53 hotspot mutant R273H and cancer drug resistance. Yet, the underlying mechanisms remain elusive. We report herewith that globotriaosylceramide (Gb3) is associated with cSrc kinase in GEMs and plays a crucial role in modulating expression of p53 R273H mutant and drug resistance. Colon cancer cell lines, either WiDr homozygous for missense‐mutated TP53 (R273H+/+) or SW48/TP53‐Dox bearing heterozygous TP53 mutant (R273H/+), display drug resistance with increased ceramide glycosylation. Inhibition of GCS with Genz‐161 (GENZ 667161) resensitized cells to apoptosis in these p53 mutant‐carrying cancer cells. Genz‐161 effectively inhibited GCS activity, and substantially suppressed the elevated Gb3 levels seen in GEMs of p53‐mutant cells exposed to doxorubicin. Complex formation between Gb3 and cSrc in GEMs to activate β‐catenin was detected in both cultured cells and xenograft tumors. Suppression of ceramide glycosylation significantly decreased Gb3‐cSrc in GEMs, β‐catenin, and methyltransferase‐like 3 for m6A RNA methylation, thus altering pre‐mRNA splicing, resulting in upregulated expression of wild‐type p53 protein, but not mutants, in cells carrying p53 R273H. Altogether, increased Gb3‐cSrc complex in GEMs of membranes in response to anticancer drug induced cell stress promotes expression of p53 mutant proteins and accordant cancer drug resistance.

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Glycosphingolipid metabolism in cell fate specification

Cited by 70 publications

References 120 publications

Hyperoxic Exposure Caused Lung Lipid Compositional Changes in Neonatal Mice

Hyperoxic Exposure Caused Lung Lipid Compositional Changes in Neonatal Mice

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

Gb3‐cSrc complex in glycosphingolipid‐enriched microdomains contributes to the expression of p53 mutant protein and cancer drug resistance via β‐catenin–activated RNA methylation

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