Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis
Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis
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DOI：
10.1021/bi0612824
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发表时间：
2007-01-16
期刊：
影响因子：
2.9
通讯作者：
Futaki, Shiroh
中科院分区：
文献类型：
--
作者：
Nakase, Ikuhiko;Tadokoro, Akiko;Futaki, Shiroh
富含精氨酸的肽，包括八精氨酸（R8）、HIV-1达特和支链富含精氨酸的肽，属于将各种蛋白质和大分子递送至细胞的主要类别之一。内吞途径的重要性最近已被证明在这些肽的细胞摄取。我们以前已经表明，巨胞饮是细胞摄取的主要途径之一，组织的F-肌动蛋白伴随着这个过程。在这项研究中，使用蛋白聚糖缺陷的CHO细胞，我们已经证明，膜相关的蛋白聚糖是必不可少的诱导肌动蛋白组织和巨胞饮摄取的精氨酸丰富的肽。我们还证明了达特肽的细胞摄取高度依赖于硫酸乙酰肝素蛋白聚糖（HSPG），而R8肽摄取较少依赖于HSPG。这表明肽的结构可能决定了HSPG的特异性，并且HSPG不是巨胞饮作用的唯一受体。对富含精氨酸的支链肽在细胞摄取中的HSPG特异性的比较表明，肽的电荷密度可能决定了特异性。在肽处理后几分钟内观察到Rac蛋白的活化和肌动蛋白的组织化。这些数据有力地表明了这样的可能性，即富含精氨酸的肽与膜相关蛋白聚糖的相互作用迅速激活细胞内信号并诱导肌动蛋白组织和巨胞饮细胞炎。
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.