Trends in Biochemical Sciences
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]
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