Monosialoganglioside GM1 Deficiency Inhibits the Neurotrophic Effects of GDNF by Disrupting Lipid Raft Assembly

Abstract Recent studies have shown that monosialoganglioside GM1 deficiency can inhibit the signal transduction process of glial cell line-derived neurotrophic factor (GDNF), which plays an important role in the pathogenesis of Parkinson's disease (PD). However, its specific mechanism still needs to be explored. We inhibited the expression of GM1 by treating cells with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). CCK-8 assay, EdU cell proliferation assay and Western blot assay were used to evaluate the effect of GM1 deficiency on the proliferation and differentiation of SH-SY5Y cells induced by GDNF and on the GDNF-RET signaling pathway. Lipid rafts were isolated by Triton X-100 solubilization and OptiPrepTM density gradient centrifugation. The alterations of lipid raft assembly and the translocation of RET into lipid rafts were evaluated after PDMP treatment. We found that PDMP treatment inhibited the proliferation and differentiation of SH-SY5Y cells induced by GDNF and reduced the phosphorylation of RET and its downstream signaling molecules Erk and Akt. In addition, after PDMP treatment, caveolin-1 and flotillin-1, the prototypical markers of lipid rafts, diffused from lipid rafts to non-lipid raft microdomains, and GDNF-induced RET translocation into lipid rafts was also reduced. These alterations could be partially reversed by adding exogenous GM1. Our results suggest that ganglioside GM1 deficiency could compromise the neurotrophic effects and signals downstream of GDNF by altering the assembly of lipid raft membrane microdomains.

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Palmitoylation of the Autographa californica Multicapsid Nucleopolyhedrovirus Envelope Glycoprotein GP64: Mapping, Functional Studies, and Lipid Rafts

Journal of Virology ◽

10.1128/jvi.77.11.6265-6273.2003 ◽

2003 ◽

Vol 77 (11) ◽

pp. 6265-6273 ◽

Cited By ~ 27

Author(s):

Sandy Xiaoxin Zhang ◽

Yu Han ◽

Gary W. Blissard

Keyword(s):

Cell Surface ◽

Lipid Rafts ◽

Lipid Raft ◽

Envelope Glycoprotein ◽

Cysteine Residue ◽

Autographa Californica ◽

Membrane Microdomains ◽

Sf9 Cells ◽

Wild Type ◽

Lipid Raft Microdomains

ABSTRACT Budded virions (BV) of the baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) contain a major envelope glycoprotein known as GP64, which was previously shown to be palmitoylated. In the present study, we used truncation and amino acid substitution mutations to map the palmitoylation site to cysteine residue 503. Palmitoylation of GP64 was not detected when Cys503 was replaced with alanine or serine. Palmitoylation-minus forms of GP64 were used to replace wild-type GP64 in AcMNPV, and these viruses were used to examine potential functions of GP64 palmitoylation in the context of the infection cycle. Analysis by immunoprecipitation and cell surface studies revealed that palmitoylation of GP64 did not affect GP64 synthesis or its transport to the cell surface in Sf9 cells. GP64 proteins lacking palmitoylation also mediated low-pH-triggered membrane fusion in a manner indistinguishable from that of wild-type GP64. Cells infected with viruses expressing palmitoylation-minus forms of GP64 produced infectious virions at levels similar to those from cells infected with wild-type AcMNPV. In combination, these data suggest that virus entry and exit in Sf9 cells were not significantly affected by GP64 palmitoylation. To determine whether GP64 palmitoylation affected the association of GP64 with membrane microdomains, the potential association of GP64 with lipid raft microdomains was examined. These experiments showed that: (i) AcMNPV-infected Sf9 cell membranes contain lipid raft microdomains, (ii) GP64 association with lipid rafts was not detected in infected Sf9 cells, and (iii) GP64 palmitoylation did not affect the apparent exclusion of GP64 from lipid raft microdomains.

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Lipid raft integrity affects GABAA receptor, but not NMDA receptor modulation by psychopharmacological compounds

The International Journal of Neuropsychopharmacology ◽

10.1017/s146114571200140x ◽

2013 ◽

Vol 16 (6) ◽

pp. 1361-1371 ◽

Cited By ~ 16

Author(s):

Caroline Nothdurfter ◽

Sascha Tanasic ◽

Barbara Di Benedetto ◽

Manfred Uhr ◽

Eva-Maria Wagner ◽

...

Keyword(s):

Nmda Receptor ◽

Lipid Rafts ◽

Gabaa Receptor ◽

Lipid Raft ◽

Tricyclic Antidepressant ◽

Membrane Microdomains ◽

Cholesterol Depletion ◽

Receptor Modulation ◽

Gabaa Receptor Subunits ◽

Triton X

Abstract Lipid rafts have been shown to play an important role for G-protein mediated signal transduction and the function of ligand-gated ion channels including their modulation by psychopharmacological compounds. In this study, we investigated the functional significance of the membrane distribution of NMDA and GABAA receptor subunits in relation to the accumulation of the tricyclic antidepressant desipramine (DMI) and the benzodiazepine diazepam (Diaz). In the presence of Triton X-100, which allowed proper separation of the lipid raft marker proteins caveolin-1 and flotillin-1 from the transferrin receptor, all receptor subunits were shifted to the non-raft fractions. In contrast, under detergent-free conditions, NMDA and GABAA receptor subunits were detected both in raft and non-raft fractions. Diaz was enriched in non-raft fractions without Triton X-100 in contrast to DMI, which preferentially accumulated in lipid rafts. Impairment of lipid raft integrity by methyl-β-cyclodextrine (MβCD)-induced cholesterol depletion did not change the inhibitory effect of DMI at the NMDA receptor, whereas it enhanced the potentiating effect of Diaz at the GABAA receptor at non-saturating concentrations of GABA. These results support the hypothesis that the interaction of benzodiazepines with the GABAA receptor likely occurs outside of lipid rafts while the antidepressant DMI acts on ionotropic receptors both within and outside these membrane microdomains.

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Membrane lipid rafts are required for D2 dopamine receptor signaling

European Psychiatry ◽

10.1016/s0924-9338(11)72615-3 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 910-910 ◽

Cited By ~ 1

Author(s):

D. Sibley ◽

L. Hazelwood ◽

R. Roof ◽

R.B. Free ◽

Y. Han ◽

...

Keyword(s):

Dopamine Receptor ◽

Lipid Rafts ◽

Lipid Raft ◽

Gradient Centrifugation ◽

Membrane Lipid ◽

Receptor Protein ◽

Membrane Microdomains ◽

Membrane Cholesterol ◽

Camp Accumulation ◽

D2 Dopamine Receptor

IntroductionLipid rafts are specialized membrane microdomains enriched in cholesterol and sphingolipids and are important in the organization of receptor-protein complexes and the regulation of signaling.Objective/aimsGiven the emerging significance of lipids with respect to receptor structure and activation, we investigated the role of lipid rafts and membrane cholesterol on D2 dopamine receptor (DAR) signaling. As the D2 DAR is the molecular target for all antipsychotic drugs, more information about its signaling may help refine therapeutics for schizophrenia.MethodsD2 DAR constructs were expressed in HEK293T cells. Sucrose density fractionation resolved lipid rafts from other membrane components. Methyl-β-cyclodextrin (MCD) was used to deplete membrane cholesterol and to disrupt lipid rafts.ResultsDetergent solubilization followed by sucrose gradient centrifugation resolved lipid rafts from heavier membrane fractions. The D2 DAR was equally distributed amongst both the lipid raft and heavier membrane fractions. Pretreatment with MCD, however, eliminated both lipid raft markers and the D2 DAR from lipid raft fractions, although the receptor was still found in heavier membrane fractions. We also found that MCD treatment abolished D2 DAR-mediated inhibition of cAMP accumulation. In contrast D1 DAR-stimulated cAMP accumulation was unaffected by MCD treatment.ConclusionsOur current results show that the D2 DAR is distributed in multiple membrane microdomains, including cholesterol-rich lipid rafts. We found that extraction of cholesterol disrupted lipid rafts and also an eliminated D2 DAR-mediated signaling. Thus, we hypothesize that lipid rafts are critical for D2 DAR signaling to occur.

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Involvement of Cholesterol-Rich Lipid Rafts in Interleukin-6-Induced Neuroendocrine Differentiation of LNCaP Prostate Cancer Cells

Endocrinology ◽

10.1210/en.2003-0772 ◽

2004 ◽

Vol 145 (2) ◽

pp. 613-619 ◽

Cited By ~ 45

Author(s):

Jayoung Kim ◽

Rosalyn M. Adam ◽

Keith R. Solomon ◽

Michael R. Freeman

Keyword(s):

Prostate Cancer ◽

Signal Transduction ◽

Lipid Rafts ◽

Lipid Raft ◽

Neuron Specific Enolase ◽

Membrane Microdomains ◽

Membrane Rafts ◽

Lncap Cells ◽

Discontinuous Sucrose Gradient ◽

Triton X

Abstract IL-6 is an inflammatory cytokine that has been linked to aggressive prostate cancer (PCa). Previous studies have demonstrated that IL-6 can enhance the differentiation of PCa cells toward a neuroendocrine (NE) phenotype, a possible indicator of hormone-refractory disease. In this report, we present evidence that the mechanism of IL-6-stimulated NE differentiation employs a detergent-resistant (lipid raft) membrane compartment for signal transduction in LNCaP PCa cells. Signal transducer and activator of transcription (STAT)3, a mediator of IL-6 signaling, was rapidly phosphorylated and translocated to the nucleus in LNCaP cells treated with IL-6. Both processes were inhibited by filipin, a cholesterol-binding compound that disrupts plasma membrane lipid rafts. Isolation of Triton X-100-insoluble raft fractions from LNCaP cells by discontinuous sucrose gradient centrifugation demonstrated that the 80-kDa IL-6 receptor localized almost exclusively to the raft compartment. Although STAT3 was located predominantly in the Triton X-100-soluble subcellular fraction in exponentially growing cells, abundant phosphorylated STAT3 was detected in the raft fraction after stimulation with IL-6. Increases in expression of the NE marker, neuron-specific enolase, and neuron-specific enolase promoter activity after IL-6 treatment were reduced after membrane rafts were disrupted by filipin treatment. LNCaP cells expressed the raft-resident proteins flotillin-2 and Giα2, but notably not caveolins, the predominant structural protein present in caveolar membrane rafts in many tissues and tumor cells. These results are the first to define a role for lipid raft membrane microdomains in signal transduction mechanisms capable of promoting the NE phenotype in PCa cells, and they demonstrate that the raft compartment is capable of mediating such signals in the absence of caveolins. Our results also suggest a mechanistic role for membrane cholesterol in cell signaling events relevant to PCa progression.

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Mediators of innate immune recognition of bacteria concentrate in lipid rafts and facilitate lipopolysaccharide-induced cell activation

Journal of Cell Science ◽

10.1242/jcs.115.12.2603 ◽

2002 ◽

Vol 115 (12) ◽

pp. 2603-2611 ◽

Cited By ~ 7

Author(s):

Martha Triantafilou ◽

Kensuke Miyake ◽

Douglas T. Golenbock ◽

Kathy Triantafilou

Keyword(s):

Lipid Rafts ◽

Lipid Raft ◽

Cell Activation ◽

Imaging Techniques ◽

Recognition System ◽

Innate Immune ◽

Membrane Microdomains ◽

Immune Recognition ◽

Cellular Activation ◽

Signalling Molecules

The plasma membrane of cells is composed of lateral heterogeneities,patches and microdomains. These membrane microdomains or lipid rafts are enriched in glycosphingolipids and cholesterol and have been implicated in cellular processes such as membrane sorting and signal transduction. In this study we investigated the importance of lipid raft formation in the innate immune recognition of bacteria using biochemical and fluorescence imaging techniques. We found that receptor molecules that are implicated in lipopolysaccharide (LPS)-cellular activation, such as CD14, heat shock protein(hsp) 70, 90, Chemokine receptor 4 (CXCR4), growth differentiation factor 5(GDF5) and Toll-like receptor 4 (TLR4), are present in microdomains following LPS stimulation. Lipid raft integrity is essential for LPS-cellular activation, since raft-disrupting drugs, such as nystatin or MCD, inhibit LPS-induced TNF-α secretion. Our results suggest that the entire bacterial recognition system is based around the ligation of CD14 by bacterial components and the recruitment of multiple signalling molecules, such as hsp70, hsp90, CXCR4, GDF5 and TLR4, at the site of CD14-LPS ligation, within the lipid rafts.

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Lipid rafts mediate internalization of β1-integrin in migrating intestinal epithelial cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00082.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. G965-G976 ◽

Cited By ~ 44

Author(s):

Elena V. Vassilieva ◽

Kirsten Gerner-Smidt ◽

Andrei I. Ivanov ◽

Asma Nusrat

Keyword(s):

Epithelial Cells ◽

Lipid Rafts ◽

Lipid Raft ◽

Intestinal Epithelial Cells ◽

Focal Adhesions ◽

Endocytic Pathway ◽

Dependent Manner ◽

Intestinal Epithelial ◽

Caveolin 1 ◽

Cell Matrix

Intestinal mucosal inflammation is associated with epithelial wounds that rapidly reseal by migration of intestinal epithelial cells (IECs). Cell migration involves cycles of cell-matrix adhesion/deadhesion that is mediated by dynamic turnover (assembly and disassembly) of integrin-based focal adhesions. Integrin endocytosis appears to be critical for deadhesion of motile cells. However, mechanisms of integrin internalization during remodeling of focal adhesions of migrating IECs are not understood. This study was designed to define the endocytic pathway that mediates internalization of β1-integrin in migrating model IECs. We observed that, in SK-CO15 and T84 colonic epithelial cells, β1-integrin is internalized in a dynamin-dependent manner. Pharmacological inhibition of clathrin-mediated endocytosis or macropinocytosis and small-interfering RNA (siRNA)-mediated knock down of clathrin did not prevent β1-integrin internalization. However, β1-integrin internalization was inhibited following cholesterol extraction and after overexpression of lipid raft protein, caveolin-1. Furthermore, internalized β1-integrin colocalized with the lipid rafts marker cholera toxin, and siRNA-mediated knockdown of caveolin-1 and flotillin-1/2 increased β1-integrin endocytosis. Our data suggest that, in migrating IEC, β1-integrin is internalized via a dynamin-dependent lipid raft-mediated pathway. Such endocytosis is likely to be important for disassembly of integrin-based cell-matrix adhesions and therefore in regulating IEC migration and wound closure.

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Lipid raft adhesion receptors and Syk regulate selectin-dependent rolling under flow conditions

Blood ◽

10.1182/blood-2006-04-013912 ◽

2006 ◽

Vol 108 (10) ◽

pp. 3352-3359 ◽

Cited By ~ 62

Author(s):

Claire Abbal ◽

Martine Lambelet ◽

Debora Bertaggia ◽

Carole Gerbex ◽

Manuel Martinez ◽

...

Keyword(s):

Tyrosine Kinase ◽

Lipid Rafts ◽

Lipid Raft ◽

Chelating Agents ◽

Regulatory Mechanisms ◽

Membrane Microdomains ◽

Leukocyte Rolling ◽

Flow Conditions ◽

Cell Rolling ◽

Pharmacologic Inhibitors

Abstract Selectins and their ligand P-selectin glycoprotein ligand-1 (PSGL-1) mediate leukocyte rolling along inflamed vessels. Cell rolling is modulated by selectin interactions with their ligands and by topographic requirements including L-selectin and PSGL-1 clustering on tips of leukocyte microvilli. Lipid rafts are cell membrane microdomains reported to function as signaling platforms. Here, we show that disruption of leukocyte lipid rafts with cholesterol chelating agents depleted raft-associated PSGL-1 and L-selectin and strongly reduced L-, P-, and E-selectin–dependent rolling. Cholesterol repletion reversed inhibition of cell rolling. Importantly, leukocyte rolling on P-selectin induced the recruitment of spleen tyrosine kinase (Syk), a tyrosine kinase associated to lipid raft PSGL-1. Furthermore, inhibition of Syk activity or expression, with pharmacologic inhibitors or by RNA interference, strongly reduced leukocyte rolling on P-selectin, but not on E-selectin or PSGL-1. These observations identify novel regulatory mechanisms of leukocyte rolling on selectins with a strong dependency on lipid raft integrity and Syk activity.

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The Role of Lipid Rafts in the Assembly and Down-Regulation of the Factor X Activating Complex on the Activated Platelet Membrane.

Blood ◽

10.1182/blood.v106.11.1010.1010 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1010-1010 ◽

Cited By ~ 1

Author(s):

Syed S. Ahmad ◽

Ya-Chi Su ◽

Peter N. Walsh

Keyword(s):

Lipid Rafts ◽

Gradient Centrifugation ◽

Early Time ◽

Sucrose Density Gradient ◽

Platelet Membrane ◽

Membrane Microdomains ◽

Factor X ◽

Sucrose Density Gradient Centrifugation ◽

Time Points ◽

Substrate Complex

Abstract In a recent study of the role of detergent-insoluble platelet membrane microdomains (lipid rafts) in the assembly of the factor X (FX) activating complex, we have shown, contrary to expectations, that the formation of lipid rafts after incubation of platelets with the thrombin receptor activation peptide (SFLLRN, 25 μM, for 30 min) results in the down-regulation, rather than assembly, of the enzyme-cofactor-substrate complex by sequestering FVIIIa and FX in rafts and separating them from FIXa, which is excluded from raft fractions isolated by sucrose density gradient centrifugation of triton X-100 (0.25%) solubilized platelets. Since the FX-activating complex is assembled rapidly on platelets after incubation with low concentrations of either thrombin (>1 nM) or SFLLRN (25 μM), we have now examined the kinetics of FX-activation complex assembly at early time points after exposure of platelets to agonists. Washed and gel-filtered human platelets, activated with SFLLRN (25 μM) in the presence of FVIIIa (5 U/ml, 1.5 nM) and FX (125 nM) rapidly (within 2 min) developed the capacity to support maximal rates of FIXa (1 nM) catalyzed FX activation that was transient and decayed to baseline within 5 min after exposure to agonist. At these early time points (0.5, 1 and 2 min), platelets activated with SFLLRN (25 μM) in the presence of 125I-labled FVIIIa (nM), FIXa (nM) or FX (nM) and analyzed by sucrose density gradient centrifugation after solubilization in triton X-100 (0.25%) were shown to sequester within the raft fractions ~15% of FIXa, ~15% of FVIIIa and ~15% of FX, whereas at later time points (5–30 min) only FVIIIa (~25%) and FX (~45%) were localized in rafts, from which FIXa was completely excluded. These results strongly suggest that platelet membrane microdomains (lipid rafts) form rapidly after exposure of platelets to PAR-1 agonists to colocalize the enzyme-cofactor-substrate complex, which is transient since at later time points FIXa dissociates from rafts that sequester the FVIIIa-FX complex to down-regulate FX activation.

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Modulation of Tissue Factor-Factor VIIa Signaling by Lipid Rafts and Caveolae.

Blood ◽

10.1182/blood.v108.11.1744.1744 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1744-1744

Author(s):

Vineet Awasthi ◽

Samir Mandal ◽

Veena Papanna ◽

L. Vijaya Mohan Rao ◽

Usha Pendurthi

Keyword(s):

Cell Signaling ◽

Lipid Rafts ◽

G Proteins ◽

Intracellular Signaling ◽

Factor Viia ◽

Membrane Microdomains ◽

Caveolin 1 ◽

Intracellular Signaling Pathways ◽

Plasma Membrane Microdomains

Abstract Tissue factor (TF) is a cellular receptor for clotting factor VIIa (VIIa) and the formation of TF-VIIa complexes on cell surfaces not only triggers the coagulation cascade but also transduces cell signaling via activation of protease-activated receptors (PARs), particularly PAR2. Although a number of recent studies provide valuable information on intracellular signaling pathways that are activated by TF-VIIa, the role of various cell surface components in mediating the interaction of TF-VIIa with PARs, and the subsequent signal transmittance are unknown. Unlike thrombin and trypsin, VIIa has to bind to its cellular receptor (TF) to activate PARs. The inability of TF-VIIa to effectively activate Ca2+ signaling and failure to desensitize the signaling to subsequently added trypsin suggest that the TF-VIIa is a poor activator of PAR2. Despite this, a number of studies have shown that VIIa is as effective as trypsin or PAR2 agonist peptide in activating intracellular signaling pathways and gene expression in cells expressing TF. Although the potential mechanism for this phenomenon is unknown, compartmentalization of TF, PAR2, and G-proteins in plasma membrane microdomains could facilitate a robust TF-VIIa-induced PAR2-mediated cell signaling. Although certain G-protein coupled receptors and G-proteins are known to be segregated into specialized membrane microdomains, lipid rafts and caveolae, little is known whether PARs are segregated into lipid rafts and caveolae, and how such segregation might influence their activation by TF-VIIa and the subsequent coupling to G-proteins. To obtain answers to some of these questions, in the present study, we have characterized TF and PAR2 distribution on tumor cell surfaces and investigated the role of lipid raft/caveolae in modulating the TF-VIIa signaling in tumor cells. Detergent extraction of cells followed by fractionation on sucrose gradient centrifugation showed that TF and PAR2 were distributed both in lipid rafts (low-density) and soluble fractions. Immunofluorescence confocal microscopy revealed that TF at the cell surface is localized in discrete plasma membrane microdomains, and colocalized with caveolin-1, a structural integral protein of caveolae, indicating caveolar localization of TF. Similar to TF, PAR2 also displayed significant punctuate staining and colocalization with caveloin-1. Further, a substantial fraction of TF and PAR2 was colocalized in caveolae. Disruption of lipid rafts/caveolae by ß-methyl cyclodextrin or filipin treatments reduced TF association with PAR2 in lipid rafts and caveolar fractions and impaired the TF-VIIa-induced cell signaling (PI hydrolysis and IL-8 gene expression). Additional studies showed that both mßCD and filipin treatments specifically impaired TF-VIIa cleavage of PAR2 and but had no significant effect on trypsin cleavage of PAR2. Disruption of caveolae with caveolin-1 silencing had no effect on the TF-VIIa coagulant activity but inhibited the TF-VIIa-induced cell signaling. In summary, the data presented herein demonstrate that TF localization at the cell membrane could influence different functions of TF differently. While caveolar localization of TF had no influence in propagating the procoagulant activity of TF, it is essential in supporting the TF-VIIa-induced cell signaling.

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Association of dengue virus NS1 protein with lipid rafts

Journal of General Virology ◽

10.1099/vir.0.83620-0 ◽

2008 ◽

Vol 89 (10) ◽

pp. 2492-2500 ◽

Cited By ~ 58

Author(s):

Sansanee Noisakran ◽

Thanyaporn Dechtawewat ◽

Panisadee Avirutnan ◽

Taroh Kinoshita ◽

Uamporn Siripanyaphinyo ◽

...

Keyword(s):

Cell Surface ◽

Dengue Virus ◽

Lipid Rafts ◽

Transmembrane Domain ◽

Gradient Centrifugation ◽

Ns1 Protein ◽

Replication Complex ◽

Infected Cells ◽

A Minor ◽

Triton X

During the replication of dengue virus, a viral non-structural glycoprotein, NS1, associates with the membrane on the cell surface and in the RNA replication complex. NS1 lacks a transmembrane domain, and the mechanism by which it associates with the membrane remains unclear. This study aimed to investigate whether membrane-bound NS1 is present in lipid rafts in dengue virus-infected cells. Double immunofluorescence staining of infected HEK-293T cells revealed that NS1 localized with raft-associated molecules, ganglioside GM1 and CD55, on the cell surface. In a flotation gradient centrifugation assay, a small proportion of NS1 in Triton X-100 cell lysate consistently co-fractionated with raft markers. Association of NS1 with lipid rafts was detected for all four dengue serotypes, as well as for Japanese encephalitis virus. Analysis of recombinant NS1 forms showed that glycosylated NS1 dimers stably expressed in HEK-293T cells without an additional C-terminal sequence, or with a heterologous transmembrane domain, failed to associate with lipid rafts. In contrast, glycosylphosphatidylinositol-linked recombinant NS1 exhibited a predilection for lipid rafts. These results indicate an association of a minor subpopulation of NS1 with lipid rafts during dengue virus infection and suggest that modification of NS1, possibly lipidation, is required for raft association.

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