The Organizing Potential of Sphingolipids in Intracellular Membrane Transport

Holthuis, Joost C. M.; Pomorski, Thomas; Raggers, R. J.; Sprong, H.; Meer, Gerrit van

doi:10.1152/physrev.2001.81.4.1689

Cited by 286 publications

(246 citation statements)

References 431 publications

(436 reference statements)

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“…In fact, sphingolipids hold long, largely saturated acyl chains that make them pack more tightly than glycerophospholipids (31). Moreover, cholesterol and sphingolipids may contribute in stabilizing the formation of highly ordered microdomains, characterized by high values of Laurdan GP (32).…”

Section: Resultsmentioning

confidence: 99%

Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells

Parolini

Federici

Raggi

et al. 2009

Journal of Biological Chemistry

1,282

1,098

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Exosomes secreted by normal and cancer cells carry and deliver a variety of molecules. To date, mechanisms referring to tumor exosome trafficking, including release and cell-cell transmission, have not been described. To gain insight into this, exosomes purified from metastatic melanoma cell medium were labeled with a lipid fluorescent probe, R18, and analyzed by spectrofluorometry and confocal microscopy. A low pH condition is a hallmark of tumor malignancy, potentially influencing exosome release and uptake by cancer cells. Using different pH conditions as a modifier of exosome traffic, we showed (i) an increased exosome release and uptake at low pH when compared with a buffered condition and (ii) exosome uptake by melanoma cells occurred by fusion. Membrane biophysical analysis, such as fluidity and lipid composition, indicated a high rigidity and sphingomyelin/ganglioside GM3 (N-acetylneuraminylgalactosylglucosylceramide) content in exosomes released at low pH. This was likely responsible for the increased fusion efficiency. Consistent with these results, pretreatment with proton pump inhibitors led to an inhibition of exosome uptake by melanoma cells. Fusion efficiency of tumor exosomes resulted in being higher in cells of metastatic origin than in those derived from primary tumors or normal cells. Furthermore, we found that caveolin-1, a protein involved in melanoma progression, is highly delivered through exosomes released in an acidic condition. The results of our study provide the evidence that exosomes may be used as a delivery system for paracrine diffusion of tumor malignancy, in turn supporting the importance of both exosomes and tumor pH as key targets for future anti-cancer strategies.

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Section: Resultsmentioning

confidence: 99%

Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells

Parolini

Federici

Raggi

et al. 2009

Journal of Biological Chemistry

1,282

1,098

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“…Glycosphingolipids comprize a small (typically 5e10% by weight) but vital fraction of membrane lipids in eukaryotes (Holthuis et al, 2001). They provide the plasma membrane with chemical and mechanical stabilities and take part in fundamental biological processes including differentiation, cellecell interaction, and transmembrane signaling.…”

Section: Introductionmentioning

confidence: 99%

Glycolipid transfer protein: Clear structure and activity, but enigmatic function

Neumann

Opacic

Wechselberger

et al. 2008

Advances in Enzyme Regulation

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“…10 Ceramide and derived glycosphingolipids form 20% of total lipids of plasmalemma and intracellular organelle membranes. 11 Gangliosides constitute 6% by weight of total brain lipids and include four major structural series of species, constructed on a ceramide scaffold with an oligosaccharide chain containing at least one sialic acid moiety. Their formation is catalyzed by membrane-bound glycosyltransfersases in the Golgi apparatus and endoplasmic reticulum.…”

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confidence: 99%

Gangliosides and Ceramides Change in a Mouse Model of Blast Induced Traumatic Brain Injury

Woods

Colsch

Jackson

et al. 2013

ACS Chem. Neurosci.

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Explosive detonations generate atmospheric pressure changes that produce nonpenetrating blast induced "mild" traumatic brain injury (bTBI). The structural basis for mild bTBI has been extremely controversial. The present study applies matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging to track the distribution of gangliosides in mouse brain tissue that were exposed to very low level of explosive detonations (2.5−5.5 psi peak overpressure). We observed major increases of the ganglioside GM2 in the hippocampus, thalamus, and hypothalamus after a single blast exposure. Moreover, these changes were accompanied by depletion of ceramides. No neurological or brain structural signs of injury could be inferred using standard light microscopic techniques. The first source of variability is generated by the Latency between blast and tissue sampling (peak intensity of the blast wave). These findings suggest that subtle molecular changes in intracellular membranes and plasmalemma compartments may be biomarkers for biological responses to mild bTBI. This is also the first report of a GM2 increase in the brains of mature mice from a nongenetic etiology. E xplosive devices used in conflicts have increased the prevalence of blast-induced mild traumatic brain injuries (bTBI) in the U.S. military. It has been estimated that about 20% of deployed personnel have been exposed to at least one episode of bTBI. 1,2 Explosive detonations produce shock waves, blast wind and electromagnetic pulses. Primary injury is due to distortion of tissue by propagation of atmospheric pressure (AP) differential between blast overpressure and normal AP, thus compressing soft tissues (lung, GI, ear, brain), followed by reverse negative pressure leading to tearing and shearing of tissue, including veins. 3 These AP changes result in nonpenetrating mild bTBI, with physical and psychological consequences. However, behavioral manifestations of mild bTBI are often not associated with discernible structural changes in brain tissue or neurological signs, in either animal models or humans. 4−9 Diagnosis is problematic and indeed even the existence of a bTBI syndrome has been debated. 10 Ceramide and derived glycosphingolipids form 20% of total lipids of plasmalemma and intracellular organelle membranes. 11Gangliosides constitute 6% by weight of total brain lipids and include four major structural series of species, constructed on a ceramide scaffold with an oligosaccharide chain containing at least one sialic acid moiety. Their formation is catalyzed by membrane-bound glycosyltransfersases in the Golgi apparatus and endoplasmic reticulum. GM1, accounts for approximately 21% of total gangliosides, while GM2, a very minor ganglioside species, constitutes less than 0.5% of total gangliosides or 0.08% of all brain lipids. Concentration ratios of ganglioside species in intracellular membranes (e.g., Golgi apparatus and endoplasmic reticulum) and plasmalemma compartments (components of lipid rafts) appear to be tightly regulated i...

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The Organizing Potential of Sphingolipids in Intracellular Membrane Transport

Cited by 286 publications

References 431 publications

Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells

Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells

Glycolipid transfer protein: Clear structure and activity, but enigmatic function

Gangliosides and Ceramides Change in a Mouse Model of Blast Induced Traumatic Brain Injury

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