Biomedical applications of glycosylphosphatidylinositol-anchored proteins

Heider, Susanne; Dangerfield, John A.; Metzner, Christoph

doi:10.1194/jlr.r070201

Cited by 31 publications

(34 citation statements)

References 99 publications

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“…While many membrane proteins are considered high‐priority targets for biologics design, there is a dearth of structural and biochemical information on them due to the inherently high degree of difficulty in expressing and purifying membrane proteins through recombinant systems . In particular, a major obstacle to the functional investigation of structurally complex post‐translational modifications, glycosylphosphatidylinositol (GPI) anchors, is the difficulty in producing structurally defined GPI moieties and GPI‐anchored proteins . To address these limitations, a nanometer‐scale membrane vesicle such as exosome would have great utility in the investigation of biological processes involving membrane surfaces and associated membrane proteins.…”

Section: Introductionmentioning

confidence: 99%

Exosome as a Vehicle for Delivery of Membrane Protein Therapeutics, PH20, for Enhanced Tumor Penetration and Antitumor Efficacy

Hong

Nam

Koh

et al. 2017

Adv Funct Materials

103

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As biochemical and functional studies of membrane protein remain a challenge, there is growing interest in the application of nanotechnology to solve the difficulties of developing membrane protein therapeutics. Exosome, composed of lipid bilayer enclosed nanosized extracellular vesicles, is a successful platform for providing a native membrane composition. This study reports an enzymatic exosome, which harbors native PH20 hyaluronidase (Exo-PH20), which is able to penetrate deeply into tumor foci via hyaluronan degradation, allowing tumor growth inhibition and increased T cell infiltration into the tumor. This exosome-based strategy is developed to overcome the immunosuppressive and anticancer therapy-resistant tumor microenvironment, which is characterized by an overly accumulated extracellular matrix. Notably, this engineered exosome with the native glycosylphosphatidylinositol-anchored form of hyaluronidase has a higher enzymatic activity than a truncated form of the recombinant protein. In addition, the exosome-mediated codelivery of PH20 hyaluronidase and a chemotherapeutic (doxorubicin) efficiently inhibits tumor growth. This exosome is designed to degrade hyaluronan, thereby augmenting nanoparticle penetration and drug diffusion. The results thus show that this is a promising exosome-based platform that harbors not only a membrane-associated enzyme with high activity but also therapeutic payloads.

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Section: Introductionmentioning

confidence: 99%

Exosome as a Vehicle for Delivery of Membrane Protein Therapeutics, PH20, for Enhanced Tumor Penetration and Antitumor Efficacy

Hong

Nam

Koh

et al. 2017

Adv Funct Materials

103

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“…Exosome-attached EGFR-nanoantibodies approach can confer a specific selectivity to EVs against tumour cells, decreasing their EGFR-proliferative signalling pathways [145]. Hence, GPI anchors can be used to target particular proteins to EVs for biomedical applications [146] (Fig. 3).…”

Section: Disease Treatmentmentioning

confidence: 99%

Post-translational add-ons mark the path in exosomal protein sorting

Moreno-Gonzalo

Fernández-Delgado

Sánchez‐Madrid

2017

Cell. Mol. Life Sci.

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“…cruzi multigene family, encoding important virulence factors out of 1,430 members 11 . It is attached to the cell surface by a glycosylphosphatidylinositol (GPI) anchor 12 a posttranslational modification conserved among eukaryotes 13 . Proteins that will acquire GPI anchor contain two signals in their primary structure, signal peptide (SP) and GPI-addition signal peptide (GPIsp), which are located at N- and C-terminus, respectively.…”

Section: Introductionmentioning

confidence: 99%

Signal peptide recognition in Trypanosoma cruzi GP82 adhesin relies on its localization at protein N-terminus

Cordero

Cortéz

Yoshida

et al. 2019

Sci Rep

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Trypanosoma cruzi , the causative agent of Chagas disease, has a dense coat of GPI-anchored virulence factors. T . cruzi GPI-anchored adhesin GP82 is encoded by a repertoire of transcripts containing several in-frame initiation codons located up-stream from that adjacent to the predicted signal peptide (SP). Transfection of T . cruzi epimastigotes with constructs encoding GP82 starting at the SP or from the farthest up-stream methionine confirmed protein expression on the parasite cell surface, comparable to the native GP82. Proteins were fully functional, inducing parasite adhesion to HeLa cells and lysosome mobilization, events required for parasite invasion. Transgenic and native GP82 proteins showed indistinguishable electrophoretic mobility, suggesting similar processing of the SP. Deletion of SP generated a ~72 kDa protein devoid of N -linked oligosaccharides allowing irrefutable identification of GP82 precursor. SP transposition to an internal region of GP82 rendered the signal unrecognizable by the signal peptidase and incapable to direct the nascent protein for ER-membrane association. Altogether our data strongly suggests that GP82 SP fails to function as transmembrane domain and its recognition by the signal peptidase shows strict dependence on the signal localization at protein N-terminus. This report presents the first experimental characterization of the full-length GP82 and its signal peptide.

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Biomedical applications of glycosylphosphatidylinositol-anchored proteins

Cited by 31 publications

References 99 publications

Exosome as a Vehicle for Delivery of Membrane Protein Therapeutics, PH20, for Enhanced Tumor Penetration and Antitumor Efficacy

Exosome as a Vehicle for Delivery of Membrane Protein Therapeutics, PH20, for Enhanced Tumor Penetration and Antitumor Efficacy

Post-translational add-ons mark the path in exosomal protein sorting

Signal peptide recognition in Trypanosoma cruzi GP82 adhesin relies on its localization at protein N-terminus

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