Glycosylphosphatidylinositol Anchor Analogues Sequester Cholesterol and Reduce Prion Formation

Bate, Clive; Tayebi, Mourad; Williams, Alun

doi:10.1074/jbc.m110.108548

Cited by 12 publications

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“…Infection by this organism is known to be primarily mediated by the glycosylphosphatidylinositol (GPI) 5 -anchored Gal/GalNAc lectin on its cell surface (1). Indeed, GPI-anchored proteins are also known to be involved in infection and virulence of several pathogens, including Trypanosoma (2) and Leishmania (3).…”

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confidence: 99%

“…Thus, the GPI biosynthetic pathway is an important therapeutic target, provided the species-specific differences of this pathway can be appropriately exploited. As the shorter biosynthetic intermediates have recently been shown to be able to influence cell membrane organization as well as composition, the early steps of the pathway are particularly attractive targets for designing therapies (5).…”

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confidence: 99%

“…: 91-11-26704502; E-mail: sskomath@mail.jnu.ac.in or sskomath@yahoo.com. 5 The abbreviations used are: GPI, glycosylphosphatidylinositol; GlcNAc-PI, N-acetyl-D-glucosaminylphosphatidylinositol; GlcN-PI, D-glucosaminylphosphatidylinositol; GnT, glucosaminyl transferase; MBP, maltosebinding protein; n-OG, octyl-␤-glucoside; PI, phosphatidylinositol; 1,10-PO, 1,10-phenanthroline; TM, transmembrane; HPTLC, high performance thin layer chromatography.…”

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confidence: 99%

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N-Acetyl-d-glucosaminylphosphatidylinositol De-N-acetylase from Entamoeba histolytica

Ashraf¹,

Yadav²,

Sreejith

et al. 2011

Journal of Biological Chemistry

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PIG-L/GPI12 proteins are endoplasmic reticulum-resident membrane proteins involved in the second step of glycosylphosphatidylinositol anchor biosynthesis in eukaryotes. We show that the Entamoeba histolytica PIG-L protein is optimally active in the acidic pH range. The enzyme has an intrinsic low level of de-N-acetylase activity in the absence of metal and is significantly stimulated by divalent cations. Metal binding induces a large conformational change in the protein that appears to improve catalytic rates while not altering the affinity of the enzyme for its substrate.

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N-Acetyl-d-glucosaminylphosphatidylinositol De-N-acetylase from Entamoeba histolytica

Ashraf¹,

Yadav²,

Sreejith

et al. 2011

Journal of Biological Chemistry

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“…The representative compound Gly-9 influenced the membrane lipid raft microdomain, suggesting its similarity in action with antiprion compounds such as cholesterol modulators. These compounds are reported to disturb the membrane lipid raft microdomain, a possible site of PrP conversion or interaction between PrPc and PrPsc (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). However, in contrast to these compounds, Gly-9 slightly or never influenced the cell surface PrPc level and the lipid raft-associated PrPc level, but it much more prominently affected the intracellular PrPc level.…”

Section: Discussionmentioning

confidence: 73%

Efficacy and Mechanism of a Glycoside Compound Inhibiting Abnormal Prion Protein Formation in Prion-Infected Cells: Implications of Interferon and Phosphodiesterase 4D-Interacting Protein

Nishizawa

Oguma

Kawata

et al. 2014

J Virol

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A new type of antiprion compound, Gly-9, was found to inhibit abnormal prion protein formation in prion-infected neuroblastoma cells, in a prion strain-independent manner, when the cells were treated for more than 1 day. It reduced the intracellular prion protein level and significantly modified mRNA expression levels of genes of two types: interferon-stimulated genes were downregulated after more than 2 days of treatment, and the phosphodiesterase 4D-interacting protein gene, a gene involved in microtubule growth, was upregulated after more than 1 day of treatment. A supplement of interferon given to the cells partly restored the abnormal prion protein level but did not alter the normal prion protein level. This interferon action was independent of the Janus activated kinase-signal transducer and activator of transcription signaling pathway. Therefore, the changes in interferon-stimulated genes might be a secondary effect of Gly-9 treatment. However, gene knockdown of phosphodiesterase 4D-interacting protein restored or increased both the abnormal prion protein level and the normal prion protein level, without transcriptional alteration of the prion protein gene. It also altered the localization of abnormal prion protein accumulation in the cells, indicating that phosphodiesterase 4D-interacting protein might affect prion protein levels by altering the trafficking of prion protein-containing structures. Interferon and phosphodiesterase 4D-interacting protein had no direct mutual link, demonstrating that they regulate abnormal prion protein levels independently. Although the in vivo efficacy of Gly-9 was limited, the findings for Gly-9 provide insights into the regulation of abnormal prion protein in cells and suggest new targets for antiprion compounds. IMPORTANCEThis report describes our study of the efficacy and potential mechanism underlying the antiprion action of a new antiprion compound with a glycoside structure in prion-infected cells, as well as the efficacy of the compound in prion-infected animals. The study revealed involvements of two factors in the compound's mechanism of action: interferon and a microtubule nucleation activator, phosphodiesterase 4D-interacting protein. In particular, phosphodiesterase 4D-interacting protein was suggested to be important in regulating the trafficking or fusion of prion protein-containing vesicles or structures in cells. The findings of the study are expected to be useful not only for the elucidation of cellular regulatory mechanisms of prion protein but also for the implication of new targets for therapeutic development.

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“…Isolation of GPI Anchors-GPIs were isolated from PrP C by digestion with 100 g/ml proteinase K at 37°C for 24 h. The released GPIs were extracted with water-saturated butan-1-ol, washed with water, lyophilized, and stored in ethanol at 20 M. GPIs were examined by high performance thin-layer chromatography on silica gel 60 plates and probed with mAb 5AB3-11 that binds to phosphatidylinositol as described (19).…”

Section: Isolation Of Prpmentioning

confidence: 99%

Monoacylated Cellular Prion Protein Modifies Cell Membranes, Inhibits Cell Signaling, and Reduces Prion Formation

Bate

Williams²

2011

Journal of Biological Chemistry

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Prion diseases occur following the conversion of the cellular prion protein (PrP C ) into a disease related, protease-resistant isoform (PrP Sc ). In these studies, a cell painting technique was used to introduce PrP C to prion-infected neuronal cell lines (ScGT1, ScN2a, or SMB cells). The addition of PrP C resulted in increased PrP Sc formation that was preceded by an increase in the cholesterol content of cell membranes and increased activation of cytoplasmic phospholipase A 2 (cPLA 2 ). In contrast, although PrP C lacking one of the two acyl chains from its glycosylphosphatidylinositol (GPI) anchor (PrP C -G-lyso-PI) bound readily to cells, it did not alter the amount of cholesterol in cell membranes, was not found within detergent-resistant membranes (lipid rafts), and did not activate cPLA 2 . It remained within cells for longer than PrP C with a conventional GPI anchor and was not converted to PrP Sc . Moreover, the addition of high amounts of PrP C -G-lyso-PI displaced cPLA 2 from PrP Sccontaining lipid rafts, reduced the activation of cPLA 2 , and reduced PrP Sc formation in all three cell lines. In addition, ScGT1 cells treated with PrP C -G-lyso-PI did not transmit infection following intracerebral injection to mice. We propose that that the chemical composition of the GPI anchor attached to PrP C modified the local membrane microenvironments that control cell signaling, the fate of PrP C , and hence PrP Sc formation. In addition, our observations raise the possibility that pharmacological modification of GPI anchors might constitute a novel therapeutic approach to prion diseases.

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Glycosylphosphatidylinositol Anchor Analogues Sequester Cholesterol and Reduce Prion Formation

Cited by 12 publications

References 59 publications

N-Acetyl-d-glucosaminylphosphatidylinositol De-N-acetylase from Entamoeba histolytica

N-Acetyl-d-glucosaminylphosphatidylinositol De-N-acetylase from Entamoeba histolytica

Efficacy and Mechanism of a Glycoside Compound Inhibiting Abnormal Prion Protein Formation in Prion-Infected Cells: Implications of Interferon and Phosphodiesterase 4D-Interacting Protein

Monoacylated Cellular Prion Protein Modifies Cell Membranes, Inhibits Cell Signaling, and Reduces Prion Formation

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