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J. Biol. Chem., Vol. 280, Issue 15, 15300-15306, April 15, 2005
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Cellular Uptake of Unconjugated TAT Peptide Involves Clathrin-dependent Endocytosis and Heparan Sulfate Receptors*
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From the
UMR 5124 CNRS, Université Montpellier 2, place Eugène Bataillon, 34095 Montpellier cedex 5, France and ¶Section on Membrane Biology, Laboratory of Cellular and Molecular Biophysics, NICHD, National Institutes of Health, Bethesda, Maryland 20892-1855
Delivery of macromolecules mediated by protein transduction domains (PTDs) attracts a lot of interest due to its therapeutic and biotechnological potential. A major reevaluation of the mechanism of PTD-mediated internalization and the role of endocytosis in this mechanism has been recently initiated. Here, we demonstrate that the entry of TAT peptide (one of the most widely used PTDs) into different primary cells is ATPand temperature-dependent, indicating the involvement of endocytosis. Specific inhibitors of clathrin-dependent endocytosis partially inhibit TAT peptide uptake, implicating this pathway in TAT peptide entry. In contrast, the caveolin-dependent pathway is not essential for the uptake of unconjugated TAT peptide as evidenced by the efficient internalization of TAT in the presence of the known inhibitors of raft/caveolin-dependent pathway and for cells lacking or deficient in caveolin-1 expression. Whereas a significant part of TAT peptide uptake involves heparan sulfate receptors, efficient internalization of peptide is observed even in their absence, indicating the involvement of other receptors. Our results suggest that unconjugated peptide might follow endocytic pathways different from those utilized by TAT peptide conjugated to different proteins.
Received for publication, February 13, 2004 , and in revised form, December 20, 2004.
* This work has been supported by grants from the Association pour la Recherche contre le Cancer (5919) and from the European Commission (QLK3-CT-2002-01989) (to B. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Both authors contributed equally to this work.
|| To whom correspondence should be addressed: NICHD, National Institutes of Health, 10 Center Dr., Bldg. 10, Rm. 10D05, Bethesda, MD 20892. Tel.: 301-402-9010; Fax: 301-480-2412; E-mail: melikovk{at}mail.nih.gov.
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