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The membrane repair response masks membrane disturbances caused by cell-penetrating peptide uptake
Stockholm University, Faculty of Science, Department of Neurochemistry.
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2009 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, no 1, 214-223 p.Article in journal (Refereed) Published
Abstract [en]

Although cell-penetrating peptides are able to deliver cargo into cells, their uptake mechanism is still not fully understood and needs to be elucidated to improve their delivery efficiency. Herein, we present evidence of a new mechanism involved in uptake, the membrane repair response. Recent studies have suggested that there might be a direct penetration of peptides in parallel with different forms of endocytosis. The direct penetration of hydrophilic peptides through the hydrophobic plasma membrane, however, is highly controversial. Three proteins involved in target cell apoptosis—perforin, granulysin, and granzymes—share many features common in uptake of cell-penetrating peptides (e.g., they bind proteoglycans). During perforin uptake, the protein activates the membrane repair response, a resealing mechanism triggered in cells with injured plasma membrane, because of extracellular calcium influx. On activation of the membrane repair response, internal vesicles are mobilized to the site of the disrupted plasma membrane, resealing it within seconds. In this study, we have used flow cytometry, fluorescence, and electron microscopy, together with high-performance liquid chromatography and mass spectrometry, to present evidence that the membrane repair response is able to mask damages caused during cell-penetrating peptide uptake, thus preventing leakage of endogenous molecules out of the cell.—Palm-Apergi, C., Lorents, A., Padari, K., Pooga, M., and Hällbrink, M. The membrane repair response masks membrane disturbances caused by cell-penetrating peptide uptake.

Place, publisher, year, edition, pages
2009. Vol. 23, no 1, 214-223 p.
Keyword [en]
protein transduction domains, perforin, granzyme B, granulysin, cellular wound healing
National Category
URN: urn:nbn:se:su:diva-25532DOI: 10.1096/fj.08-110254ISI: 000262095500024OAI: diva2:199913
Available from: 2008-10-23 Created: 2008-10-07 Last updated: 2015-03-09Bibliographically approved
In thesis
1. Design and evaluation of drug delivery vehicles
Open this publication in new window or tab >>Design and evaluation of drug delivery vehicles
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A crucial aspect of drug delivery is efficient transport to the site of action. Thus, there is a need to design and evaluate new delivery vehicles. In this thesis two delivery vehicles, cell-penetrating peptides and bacterial ghosts, were evaluated. The understanding of the internalization and degradation kinetics of cell-penetrating peptides is important for the practical aspects of cargo delivery since peptides have a notorious reputation of being rapidly degraded. If the cell-penetrating peptide remains intact inside the cellular environment, there is a possibility that the peptide-cargo conjugate leaks back to the extracellular environment. However, if it is degraded outside the cell, the cargo will never be delivered. In order to improve uptake efficiency and to be able to foresee side effects, the translocation mechanism needs to be fully elucidated. Data gathered from the first two papers led to the proposal of a new me-chanism involved in cell-penetrating peptide uptake: the membrane repair response, a resealing mechanism rapidly patching up broken membranes. This mechanism could explain the divergence in perception concerning the uptake pathways. Furthermore a new assay to produce the second delivery vehicle, bacterial ghosts, was developed based on data from the cell-penetrating peptide investigations. Bacterial ghosts are dead bacteria devoid of cytoplasmic contents but still retaining their structural and morphological characteristics, after protein E lysis of the bacterial cell membrane. By using a cell-penetrating peptide with antimicrobial effects, a new rapid peptide-based strategy to produce ghosts was developed and the capability to deliver plasmid DNA into the cell for expression was evaluated.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi, 2008. 77 p.
National Category
Research subject
Neurochemistry and Neurotoxicology
urn:nbn:se:su:diva-8256 (URN)978-91-7155-754-4 (ISBN)
Public defence
2008-11-14, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00
Available from: 2008-10-23 Created: 2008-10-07Bibliographically approved

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