Inducible Membrane Permeabilization by Attenuated Lytic Peptides: A New Concept for Accessing Cell Interiors through Ruffled Membranes

Misao Akishiba, Shiroh Futaki

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

A variety of mid-sized and large biomolecules have been used as tools to explore fundamental biological questions. However, such molecules are often cell-impermeable and thus unable to attain sufficient access to the cell interior. This inhibits their ability to yield analytical data about the cell interior or modify the cellular events. We have recently developed a peptide, engineered from a natural hemolytic peptide, named L17E. Substantial cytosolic delivery of biomacromolecules, including antibodies, was attained in the presence of this peptide. In this study, detailed analysis of the modes of action of L17E was conducted, elucidating that a large fraction of the cytosolic translocation of biomacromolecules is accomplished in the presence of L17E within 5 min. L17E stimulates actin polymerization and induces a dynamic structural alteration of cell membranes, resulting in a ruffled appearance. Studies using macropinocytosis inhibitors and proteins that control endosome maturation raise the possibility that the transient permeabilization of ruffled cell membranes, rather than the rupture of endosomal membranes, is the crucial mechanism for facile cytosolic translocation of biomacromolecules in the presence of L17E. Our results provide a distinct concept of intracellular delivery, different from direct translocation through cell membranes or endocytic uptake followed by endosomal escape. This method of permeabilization via membrane ruffling provides a novel concept in intracellular delivery.

Original languageEnglish
Pages (from-to)2540-2548
Number of pages9
JournalMolecular pharmaceutics
Volume16
Issue number6
DOIs
Publication statusPublished - Jun 3 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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