Internalization of HIV-1 Tat Requires Cell Surface Heparan Sulfate Proteoglycans

Intracellular trafficking of nonviral vectors

“…Recent studies have indicated that the mode of cell entry is endocytic, 110 likely via the binding to and internalization of cell surface proteoglycans. [111][112][113] In agreement, cell entry of a nonaarginine peptide (R9) was found to be proteoglycan-mediated, as R9 was not taken up by proteoglycan-deficient CHO cells, and cell binding and entry was also inhibited by heparin. 114 Several studies have identified macropinocytosis as being the major cell entry route of TAT PTD peptides, and similar proteins, that bind proteoglycans.…”

“…123 In contrast, CHO cells, which lack T-cell-specific receptors, take up full-length TAT via proteoglycans. 113 Clearly in the examples just described, an endocytic ligand may utilize a particular cell entry route in its native context, but a vector directed by the same ligand may enter cells through a different internalization pathway. Moreover, the pathway of cell entry may or may not be conducive to gene transfer, as some routes that avoid lysosomes do not necessarily support high levels of final gene expression.…”

Arginine‐rich cell‐penetrating peptides

“…Treatment of cells with chemicals that eliminate or cleave the HS proteoglycans resulted in a significant decrease in TAT peptide internalization [40]. Studies with mutant cells that are unable to synthesize glycosaminoglycans showed reduced TATmediated transport [39,41,42]. These studies suggest that heparan sulfate can act as a receptor for TAT peptide, and constitutes an important pathway for internalization; however, none of the studies have demonstrated complete inhibition of cellular uptake [41].…”

“…Examples include the TAT peptide from the HIV transactivator protein TAT, Penetratin, a 16 amino acid domain from the Antennapedia protein of Drosophila, a flock house virus (FHV) coat peptide (sequence [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], and oligoarginines [3,5]. In this review, we focus on TAT peptide, partly because it has attracted the most attention, but also because it is a prototypical example that has many of the essential characteristics of the arginine-rich cell-penetrating peptides.…”

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

“…Except for high content of cationic aminoacids, Lys and Arg, there is little if any structural similarity between different PTDs. Tat transduction is critically dependent on the presence of the basic residues [330], and may involve binding of a cationic peptide with heparin sulfate proteoglycans at the cell surface [331], followed by internalization via lipid-raft dependent macropinocytosis [332]. Notably, the delivery process with PTD is stringent and may result in inactivation or denaturing of some PTD fusion proteins [326].…”