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This Article Full Text Full Text (PDF) All Versions of this Article: fj.08-110254v1 23/1/214    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Palm-Apergi, C. Articles by Hällbrink, M. Search for Related Content PubMed PubMed Citation Articles by Palm-Apergi, C. Articles by Hällbrink, M.

The membrane repair response masks membrane disturbances caused by cell-penetrating peptide uptake

Caroline Palm-Apergi^*,1, Annely Lorents^,, Kärt Padari^,, Margus Pooga^, and Mattias Hällbrink^*

^* Department of Neurochemistry, Arrhenius Laboratories, Stockholm University, Stockholm, Sweden;

Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; and

Estonian Biocentre, Tartu, Estonia

¹ Correspondence: Department of Neurochemistry, Stockholm University, S-106 91 Stockholm, Sweden. E-mail: caroline{at}neurochem.su.se

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.

Key Words: protein transduction domains • perforin • granzyme B • granulysin • cellular wound healing