title: Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis.
abstract: Arginine-rich peptides, including octaarginine (R8), HIV-1 Tat, and branched-chain arginine-rich peptides, belong to one of the major classes of cell-permeable peptides which deliver various proteins and macromolecules to cells. The importance of the endocytic pathways has recently been demonstrated in the cellular uptake of these peptides. We have previously shown that macropinocytosis is one of the major pathways for cellular uptake and that organization of the F-actin accompanies this process. In this study, using proteoglycan-deficient CHO cells, we have demonstrated that the membrane-associated proteoglycans are indispensable for the induction of the actin organization and the macropinocytic uptake of the arginine-rich peptides. We have also demonstrated that the cellular uptake of the Tat peptide is highly dependent on heparan sulfate proteoglycan (HSPG), whereas the R8 peptide uptake is less dependent on HSPG. This suggests that the structure of the peptides may determine the specificity for HSPG, and that HSPG is not the sole receptor for macropinocytosis. Comparison of the HSPG specificity of the branched-chain arginine-rich peptides in cellular uptake has suggested that the charge density of the peptides may determine the specificity. The activation of the Rac protein and organization of the actin were observed within a few minutes after the peptide treatment. These data strongly suggest the possibility that the interaction of the arginine-rich peptides with the membrane-associated proteoglycans quickly activates the intracellular signals and induces actin organization and macropinocytotis.
authors.affiliation: Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Ikuhiko
authors.initials: I
authors.lastname: Nakase
authors.forename: Akiko
authors.initials: A
authors.lastname: Tadokoro
authors.forename: Noriko
authors.initials: N
authors.lastname: Kawabata
authors.forename: Toshihide
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Hironori
authors.initials: H
authors.lastname: Katoh
authors.forename: Kiyo
authors.initials: K
authors.lastname: Hiramoto
authors.forename: Manabu
authors.initials: M
authors.lastname: Negishi
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Nomizu
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sugiura
authors.forename: Shiroh
authors.initials: S
authors.lastname: Futaki
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015696:Gene Products, tat / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010873:Pinocytosis; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D015696:Gene Products, tat; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; D009842:Oligopeptides; D010455:Peptides; D011509:Proteoglycans; C500307:octa-arginine peptide; D001120:Arginine