Heparan sulfate proteoglycan as a plasma membrane carrier

https://doi.org/10.1016/S0968-0004(03)00031-8Get rights and content

Abstract

The plasma membrane defines the border of living cells and provides a barrier to extracellular components. Advances in molecular biology have resulted in the development of novel therapeutic strategies (e.g. gene therapy and cellular protein delivery) which rely on the entry of charged macromolecules into the intracellular compartment. Recent reports demonstrate an intriguing role for heparan sulfate proteoglycans in cellular internalization of viruses, basic peptides and polycation–nucleic-acid complexes and the possibility that they have important implications for gene transfer and protein delivery to mammalian cells. This review focuses on heparan sulfate proteoglycan as a plasma membrane carrier.

Section snippets

The ‘on’ and ‘off’ functions of cell-surface HSPG

The biosynthesis and function of proteoglycans (PGs), and the complex structure of their glycosaminoglycan (GAG) chains have been comprehensively reviewed elsewhere 12, 13, 14. PGs encompass a heterogeneous group of proteins that are substituted with linear, polysulfated and, thereby, highly negatively charged GAG polysaccharides [e.g. heparan sulfate (HS)]. Owing to their abundant carboxyl and sulfate groups, GAGs constitute a major source of macromolecular polyanions that surround almost

Lipoproteins, growth factors and microbes require HSPGs for cellular entry

It is well-established that HS chains bind avidly to the lipid-associated proteins apolipoprotein E, lipoprotein lipase and hepatic lipase, and that lipoproteins adhere to and enter cells in a HSPG-dependent manner [18]. Both perlecan (another HSPG found in basement membranes and in the pericellular matrix) and syndecan have been implicated in the internalization and lysosomal delivery of lipoproteins 19, 20. The conclusion from these studies is that HSPGs mediate ligand internalization either

It takes a sugar to deliver nucleic acids over the cellular lipid barrier…

Mislick and Baldeschwieler [28] studied the mechanism of polylysine (56 kDa)-mediated gene transfer, and observed an optimum transfection charge ratio (lysine/nucleotide) of +1.5. Charge ratios <1 yielded low reporter gene expression, suggesting that polylysine–DNA complexes require a net positive charge for efficient transfection. As GAGs are highly anionic, the authors hypothesized that membrane-associated PGs are involved in polylysine-DNA complex internalization. Using the procedures

…and to deliver proteins

The most well-known membrane-penetrating peptide, HIV-Tat, is released from HIV-infected cells and then enters surrounding cells where it activates HIV transcription via interaction with the viral target sequence. In this way, Tat can stimulate viral particle replication in a paracrine fashion 36, 37. By genetic or chemical conjugation of Tat, efficient intracellular delivery of proteins can be achieved. Intraperitoneal injection of a Tat-β-galactosidase fusion protein (>120 kDa) in mice

Concluding remarks and future perspectives

HSPGs function as a natural entry mechanism for polyamines, viruses, polybasic peptides and polycation–nucleic acid complexes, which has several important implications.

The widespread presence of arginine/lysine-rich stretches in proteins opens up the possibility of a novel mechanism for intercellular communication in the regulation of complex biological processes. Recently, it has been shown that the herpes simplex viral-tegument peptide VP22 binds to, and transports, viral mRNA to adjacent

Acknowledgements

This work was supported by grants from the Crafoord Foundation, the Royal Physiographic Society of Lund, the Swedish Society for Medical Research and the Swedish Society of Medicine. I thank Barbara Parker and Staffan Sandgren for their excellent artwork, and Erik Eklund and Lars-Åke Fransson for many useful comments. This work was done at the Department of Cell and Molecular Biology, Section of Cell and Matrix Biology, Lund University, BMC, C-13, SE-221 84, Lund, Sweden (e-mail: [email protected]

References (48)

  • S. Sandgren

    Nuclear targeting of macromolecular polyanions by an HIV-Tat derived peptide. Role for cell-surface proteoglycans

    J. Biol. Chem.

    (2002)
  • L.C. Mounkes

    Proteoglycans mediate cationic liposome–DNA complex-based gene delivery in vitro and vivo

    J. Biol. Chem.

    (1998)
  • M. Belting et al.

    Intracellular accumulation of secreted proteoglycans inhibits cationic lipid-mediated gene transfer: co-transfer of glycosaminoglycans to the nucleus

    J. Biol. Chem.

    (1999)
  • C.M. Wiethoff

    The potential role of proteoglycans in cationic lipid-mediated gene delivery. Studies of the interaction of cationic lipid-DNA complexes with model glycosaminoglycans

    J. Biol. Chem.

    (2001)
  • M. Green et al.

    Autonomous functional domains of chemically synthesized human immunodeficiency virus Tat trans-activator protein

    Cell

    (1988)
  • A.D. Frankel et al.

    Cellular uptake of the Tat protein from human immunodeficiency virus

    Cell

    (1988)
  • M. Tyagi

    Internalization of HIV-1 Tat requires cell surface heparan sulfate proteoglycans

    J. Biol. Chem.

    (2001)
  • S. Futaki

    Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery

    J. Biol. Chem.

    (2001)
  • T. Suzuki

    Possible existence of common internalization mechanisms among arginine-rich peptides

    J. Biol. Chem.

    (2002)
  • J. Mai

    Efficiency of protein transduction is cell-type-dependent and is enhanced by dextran sulfate

    J. Biol. Chem.

    (2002)
  • F. Cheng

    Nitric oxide-dependent processing of heparan sulfate in recycling S-nitrosylated glypican-1 takes place in caveolin-1-containing endosomes

    J. Biol. Chem.

    (2002)
  • B.J. Nichols et al.

    Endocytosis without clathrin coats

    Trends Cell Biol.

    (2001)
  • A. Eguchi

    Protein transduction domain of HIV-Tat protein promotes efficient delivery of DNA into mammalian cells

    J. Biol. Chem.

    (2001)
  • R.G. Crystal

    Transfer of genes to humans: early lessons and obstacles to success

    Science

    (1995)
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