期刊
JOURNAL OF CONTROLLED RELEASE
卷 147, 期 2, 页码 171-179出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2010.06.030
关键词
Acid sphingomyelinase; Cell-penetrating peptide; Ceramide; Direct translocation; Drug delivery; Nona-arginine
资金
- Volkswagen-Foundation (Nachwuchsgruppen an Universitaten) [I/77 472]
- Radboud University Nijmegen Medical Centre
- IFORES program
Cationic cell-penetrating peptides (CPP) are receiving increasing attention as molecular transporters of membrane-impermeable molecules. Import of cationic CPP occurs both via endocytosis and at higher peptide concentrations in an endocytosis-independent manner via localized regions of the plasma membrane. At present, this endocytosis-independent import of cationic CPP is not well understood, but has been shown to be sensitive to various pharmacological inhibitors, suggesting a role of an unidentified enzymatic activity. Here, we demonstrate that the direct translocation of cationic CPP depends on a CPP-induced translocation of acid sphingomyelinase (ASMase) to the outer leaflet of the plasma membrane and ceramide formation. The involvement of ASMase in uptake was confirmed by a pharmacological inhibition of ASMase by imipramine and a subsequent rescue of uptake through external addition of sphingomyelinase, and by using ASMase-deficient cells. We also found that the threshold for direct CPP translocation can be lowered through addition of sphingomyelinase and that sphingomyelinase enhances the translocation of R9 coupled to low-molecular weight cargos, but not high-molecular weight cargos. In conclusion, we show that a previously poorly understood mechanism of cationic CPP import depends on the ASMase-dependent formation of ceramide on the outer leaflet of the plasma membrane. To our knowledge, this is the first illustration that a class of delivery vectors operates through the induction of an enzymatic activity that changes the lipid composition of the plasma membrane. (C) 2010 Elsevier B.V. All rights reserved.
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