Intracellular delivery of glutathione S-transferase-fused proteins into mammalian cells by polyethylenimine-glutathione conjugates

J Biochem. 2008 Oct;144(4):447-55. doi: 10.1093/jb/mvn087. Epub 2008 Jul 4.

Abstract

The glutathione S-transferase (GST)-fused protein expression system has been extensively used to generate a large quantity of proteins and has served for functional analysis in vitro. In this study, we developed a novel approach for the efficient intracellular delivery of GST-fused proteins into living cells to expand their usefulness up to in vivo use. Since protein cationization techniques are powerful strategies for efficient intracellular uptake by adsorptive-mediated endocytosis, GST-fused proteins were cationized by forming a complex with a polycationic polyethylenimine (PEI)-glutathione conjugate. On screening of protein transduction, optimized PEI-glutathione conjugate for protein transduction was characterized by a partly oligomerized mixture of PEI with average molecular masses of 600 (PEI600) modified with multiple glutathiones, which could have sufficient avidity for GST. Furthermore, enhanced endosomal escape of transduced GST-fused proteins was observed when they were delivered with a glutathione-conjugated PEI600 derivative possessing a hydroxybutenyl moiety. These results were confirmed by both intracellular confocal imaging of GST-fused green fluorescent protein and activation of an endogenous growth signal transduction pathway by a GST-fused constitutively active mutant of a kinase protein. These PEI-glutathione conjugates seem to be convenient molecular tools for protein transduction of widely used GST-fused proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BALB 3T3 Cells
  • Biological Transport, Active
  • CHO Cells
  • COS Cells
  • Chlorocebus aethiops
  • Cricetinae
  • Cricetulus
  • Drug Carriers
  • Endocytosis
  • Glutathione / metabolism*
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • Mice
  • Molecular Weight
  • Polyethyleneimine / chemistry
  • Polyethyleneimine / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transduction, Genetic

Substances

  • Drug Carriers
  • Recombinant Fusion Proteins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Polyethyleneimine
  • Glutathione Transferase
  • MAP Kinase Kinase 1
  • Glutathione