Dihydrosphingomyelin Impairs HIV-1 Infection by Rigidifying Liquid-Ordered Membrane Domains

Vieira, Catarina; Munoz-Olaya, Jose; Sot, Jesús; Jiménez-Baranda, Sonia; Izquierdo-Useros, Nuria; Abad, José Luı́s; Apellániz, Beatriz; Delgado, Rafaël; Martínez-Picado, Javier; Alonso, Alicia; Casas, Josefina; Nieva, José L.; Fabriás, Gemma; Mañes, Santos; Goñi, Félix M.

doi:10.1016/j.chembiol.2010.05.023

Cited by 83 publications

(55 citation statements)

References 61 publications

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“…Such domains may well be the mammalian counterparts of the yeast domains identified in this study. It was also found that dihydrosphingomyelin has an increased ability to form gel phase domains when mixed with cholesterol and mammalian phospholipids when compared with sphingomyelin with the same acyl chain (64). Dihydrosphingomyelin has a sphingoid backbone that is closer to yeast sphingolipids than sphingomyelin.…”

Section: Discussionmentioning

confidence: 90%

Gel Domains in the Plasma Membrane of Saccharomyces cerevisiae

Aresta‐Branco

Cordeiro

Marinho

et al. 2011

Journal of Biological Chemistry

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The plasma membrane of Saccharomyces cerevisiae was studied using the probes trans-parinaric acid and diphenylhexatriene. Diphenylhexatriene anisotropy is a good reporter of global membrane order. The fluorescence lifetimes of transparinaric acid are particularly sensitive to the presence and nature of ordered domains, but thus far they have not been measured in yeast cells. A long lifetime typical of the gel phase (>30 ns) was found in wild-type (WT) cells from two different genetic backgrounds, at 24 and 30°C, providing the first direct evidence for the presence of gel domains in living cells. To understand their nature and location, the study of WT cells was extended to spheroplasts, the isolated plasma membrane, and liposomes from total lipid and plasma membrane lipid extracts (with or without ergosterol extraction by cyclodextrin). It is concluded that the plasma membrane is mostly constituted by ordered domains and that the gel domains found in living cells are predominantly at the plasma membrane and are formed by lipids. To understand their composition, strains with mutations in sphingolipid and ergosterol metabolism and in the glycosylphosphatidylinositol anchor remodeling pathway were also studied. The results strongly indicate that the gel domains are not ergosterol-enriched lipid rafts; they are mainly composed of sphingolipids, possibly inositol phosphorylceramide, and contain glycosylphosphatidylinositol-anchored proteins, suggesting an important role in membrane traffic and signaling, and interactions with the cell wall. The abundance of the sphingolipid-enriched gel domains was inversely related to the cellular membrane system global order, suggesting their involvement in the regulation of membrane properties.

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Section: Discussionmentioning

confidence: 90%

Gel Domains in the Plasma Membrane of Saccharomyces cerevisiae

Aresta‐Branco

Cordeiro

Marinho

et al. 2011

Journal of Biological Chemistry

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“…It will be interesting to explore in future studies whether membrane rigidity can inhibit dihydroceramide desaturase activity and whether cells increase membrane rigidity at high cell density. Notably, in a study addressing HIV infection, it has been shown that dihydrosphingomyelin increases membrane rigidity ( 38 ). Of note is that in vitro studies have shown that dihydroceramides do not support transbilayer fl ip/fl op of lipids, whereas ceramides do ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Cell density-dependent reduction of dihydroceramide desaturase activity in neuroblastoma cells

Spassieva

Rahmaniyan

Bielawski

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.orgIn the last two decades, sphingolipids and their precursors have been extensively studied for their cell signaling roles (recently reviewed in Ref. 1 ). Changes in sphingolipid levels are shown to play a role in regulating important cellular processes, such as cell proliferation, growth arrest, and cell death. Here we investigated the role of sphingolipids in cell-cycle arrest at high cell density, a phenomenon known as contact inhibition at saturation density ( 2 ). Density-dependent inhibition in cultured cells serves as a model to study the balance between cell proliferation and growth arrest in a multicellular organism. Cell-number control is important for maintenance of tissue homeostasis within multicellular organisms, and cell-cycle arrest is a critical aspect of that control mechanism ( 2, 3 ). Cell-cycle arrest at high saturation density is a complex process dependent on multiple factors, and earlier studies have shown that sphingolipids play a role in it. Gangliosides, GM 3 in particular, have been shown to promote growth inhibition in confl uent cells ( 2,4,5 ), and a recent study has revealed that abundance of another ganglioside, GM 1 , on the cellular membrane depends on the cell's population context ( 6 ). A more recent work showed that very long chain (VLC) ceramides (i.e., ceramides with fatty acid chain length C 22 -C 26 ) also play a role in cell-cycle arrest at contact inhibition in breast cancer cells ( 7 ).Changes in sphingolipids, resulting from various cellular insults or manipulation of the sphingolipid pathway, are often complex and include simultaneous changes of several sphingolipid species ( 1,8 ). Therefore, considering the interdependency of the sphingolipid pathway, we applied a metabolic approach to decipher the role of sphingolipids in density-dependent growth arrest in neuroblastoma cells. Neuroblastoma is the most common cancer in infants and understanding its biology is important for devising new therapeutic strategies.Abstract We applied a metabolic approach to investigate the role of sphingolipids in cell density-induced growth arrest in neuroblastoma cells. Our data revealed that sphingolipid metabolism in neuroblastoma cells signifi cantly differs depending on the cells' population context. At high cell density, cells exhibited G0/G1 cell-cycle arrest and reduced ceramide, monohexosylceramide, and sphingomyelin, whereas dihydroceramide was signifi cantly increased. In addition, our metabolic-labeling experiments showed that neuroblastoma cells at high cell density preferentially synthesized very long chain (VLC) sphingolipids and dramatically decreased synthesis of sphingosine-1-phosphate (S1P). Moreover, densely populated neuroblastoma cells showed increased message levels of both anabolic and catabolic enzymes of the sphingolipid pathway. Notably, our metabolic-labeling experiments indicated reduced dihydroceramide desaturase activity at confl uence, which was confi rmed by direct measurement of dihydroceramide desat...

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“…Vieira et al (35) discovered that knockdown or pharmacological inhibition of DES1, which replaced sphingomyelins with dihydrosphingomyelins, inhibited infection by replication-competent and -deficient HIV-1 in cultured cells. The increased dihydrosphingolipid levels gave rise to more rigid membranes that were resistant to the insertion of the gp41 fusion peptide, thus inhibiting fusion of the viral and cellular membranes.…”

Section: Hiv Infectionmentioning

confidence: 99%

Dihydroceramides: From Bit Players to Lead Actors

Siddique¹,

Chaurasia

et al. 2015

Journal of Biological Chemistry

120

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Sphingolipid synthesis involves a highly conserved biosynthetic pathway that produces fundamental precursors of complex sphingolipids. The final reaction involves the insertion of a double bond into dihydroceramides to generate the more abundant ceramides, which are converted to sphingomyelins and glucosylceramides/gangliosides by the addition of polar head groups. Although ceramides have long been known to mediate cellular stress responses, the dihydroceramides that are transiently produced during de novo sphingolipid synthesis were deemed inert. Evidence published in the last few years suggests that these dihydroceramides accumulate to a far greater extent in tissues than previously thought. Moreover, they have biological functions that are distinct and non-overlapping with those of the more prevalent ceramides. Roles are being uncovered in autophagy, hypoxia, and cellular proliferation, and the lipids are now implicated in the etiology, treatment, and/or diagnosis of diabetes, cancer, ischemia/ reperfusion injury, and neurodegenerative diseases. This minireview summarizes recent findings on this emerging class of bioactive lipids.

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Dihydrosphingomyelin Impairs HIV-1 Infection by Rigidifying Liquid-Ordered Membrane Domains

Cited by 83 publications

References 61 publications

Gel Domains in the Plasma Membrane of Saccharomyces cerevisiae

Gel Domains in the Plasma Membrane of Saccharomyces cerevisiae

Cell density-dependent reduction of dihydroceramide desaturase activity in neuroblastoma cells

Dihydroceramides: From Bit Players to Lead Actors

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