Glycosaminoglycans are required for translocation of amphipathic cell-penetrating peptides across membranes

Biochim Biophys Acta. 2016 Aug;1858(8):1860-7. doi: 10.1016/j.bbamem.2016.04.010. Epub 2016 Apr 23.

Abstract

Cell-penetrating peptides (CPPs) are considered as one of the most promising tools to mediate the cellular delivery of various biologically active compounds that are otherwise cell impermeable. CPPs can internalize into cells via two different pathways - endocytosis and direct translocation across the plasma membrane. In both cases, the initial step of internalization requires interactions between CPPs and different plasma membrane components. Despite the extensive research, it is not yet fully understood, which of these cell surface molecules mediate the direct translocation of CPPs across the plasma- and endosomal membrane. In the present study we used giant plasma membrane vesicles (GPMVs) as a model membrane system to elucidate the specific molecular mechanisms behind the internalization and the role of cell surface glycosaminoglycans (GAGs) in the translocation of four well-known CPPs, classified as cationic (nona-arginine, Tat peptide) and amphipathic (transportan and TP10). We demonstrate here that GAGs facilitate the translocation of amphipathic CPPs, but not the internalization of cationic CPPs; and that the uptake is not mediated by a specific GAG class, but rather the overall amount of these polysaccharides is crucial for the internalization of amphipathic peptides.

Keywords: Cell-penetrating peptide; Direct translocation; Glycosaminoglycan; Nona-arginine; Tat peptide; Transportan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cell-Penetrating Peptides / metabolism*
  • Cricetinae
  • Cricetulus
  • Galanin / metabolism
  • Glycosaminoglycans / physiology*
  • Heparin Lyase / pharmacology
  • Humans
  • Oligopeptides / metabolism
  • Peptide Fragments / metabolism
  • Protein Transport
  • Receptors, Adrenergic, beta-1 / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Transport Vesicles / chemistry
  • Transport Vesicles / metabolism*
  • Wasp Venoms / metabolism
  • Wheat Germ Agglutinins
  • tat Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • Cell-Penetrating Peptides
  • Glycosaminoglycans
  • Oligopeptides
  • Peptide Fragments
  • Receptors, Adrenergic, beta-1
  • Recombinant Fusion Proteins
  • Wasp Venoms
  • Wheat Germ Agglutinins
  • nonaarginine
  • tat Gene Products, Human Immunodeficiency Virus
  • transportan
  • transportan-10
  • Galanin
  • Heparin Lyase