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Papers In Press, published online ahead of print August 5, 2002
J. Biol. Chem, 10.1074/jbc.M205395200
Submitted on May 31, 2002
Revised on August 5, 2002
Accepted on August 4, 2002

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

Staffan Sandgren, Fang Cheng, and Mattias Belting

Cell- and Molecular Biology, Cell- and Matrix Biology, Lund SE-221 84

Corresponding Author: Mattias.Belting{at}medkem.lu.se

New therapies, based on gene transfer and protein delivery, require a better understanding of the basic mechanisms of macromolecular membrane transport. We have studied cellular uptake of macromolecular polyanions, i.e. DNA and glycosaminoglycans, and a polybasic HIV-Tat derived peptide (GRKKRRQRRRPPQC), using fluorescence assisted cell sorting and confocal fluorescence microscopy. The Tat peptide stimulated cellular uptake of both DNA and heparan sulfate in a time-, concentration-, and temperature-dependent manner. Peptide-polyanion complexes accumulated in large, acidic, cytoplasmic vesicles, formed de novo, followed by transfer of polyanion into the nuclear compartment, and subsequent disappearance of the endolysosomal vesicles. In the absence of polyanion, the Tat peptide displayed rapid accumulation in the nuclear compartment. However, in the presence of polyanion, the peptide was almost exclusively retained in cytoplasmic vesicles. Cell-surface proteoglycans played a pivotal role in the uptake of complexes exhibiting a relatively high peptide- to polyanion ratio, corresponding to a net positive charge of the complexes. Uptake of polyanions per se or complexes with a relatively low peptide- to polyanion ratio was favored by proteoglycan deficiency in the recipient cells, indicating the existence of distinct transport mechanisms. Moreover, expression of full-length HIV-Tat as well as exogenous addition of HIV-Tat peptide resulted in cellular accumulation of endogenous proteoglycans. We conclude that an HIV-Tat derived peptide efficiently targets extraneous DNA and glycosaminoglycans to the nuclear compartment, and that proteoglycans serve a regulatory role in these processes, which may have implications for directed gene- and drug delivery in vivo.


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