Poon G M K, Gariépy J
Division of Cancer Genomics and Proteomics, Ontario Cancer Institute, University Health Network, Ontario, Canada M5G 2M9.
Biochem Soc Trans. 2007 Aug;35(Pt 4):788-93. doi: 10.1042/BST0350788.
Polycationic macromolecules and cationic peptides acting as PTDs (protein transduction domains) and CPPs (cell-penetrating peptides) represent important classes of agents used for the import and delivery of a wide range of molecular cargoes into cells. Their entry into cells is typically initiated through interaction with cell-surface HS (heparan sulfate) molecules via electrostatic interactions, followed by endocytosis of the resulting complexes. However, the endocytic mechanism employed (clathrin-mediated endocytosis, caveolar uptake or macropinocytosis), defining the migration of these peptides into cells, depends on parameters such as the nature of the cationic agent itself and complex formation with cargo, as well as the nature and distribution of proteoglycans expressed on the cell surface. Moreover, a survey of the literature suggests that endocytic pathways should not be considered as mutually exclusive, as more than one entry mechanism may be operational for a given cationic complex in a particular cell type. Specifically, the observed import may best be explained by the distribution and uptake of cell-surface HSPGs (heparan sulfate proteoglycans), such as syndecans and glypicans, which have been shown to mediate the uptake of many ligands besides cationic polymers. A brief overview of the roles of HSPGs in ligand internalization is presented, as well as mechanistic hypotheses based on the known properties of these cell-surface markers. The identification and investigation of interactions made by glycosaminoglycans and core proteins of HSPGs with PTDs and cationic polymers will be crucial in defining their uptake by cells.
作为蛋白质转导结构域（PTD）和细胞穿透肽（CPP）的聚阳离子大分子和阳离子肽，是用于将多种分子货物导入和递送至细胞的重要一类试剂。它们进入细胞通常是通过与细胞表面硫酸乙酰肝素（HS）分子通过静电相互作用开始，随后是所形成复合物的内吞作用。然而，所采用的内吞机制（网格蛋白介导的内吞作用、小窝摄取或巨胞饮作用）决定了这些肽进入细胞的迁移方式，这取决于诸如阳离子试剂本身的性质、与货物的复合物形成，以及细胞表面表达的蛋白聚糖的性质和分布等参数。此外，文献调查表明内吞途径不应被视为相互排斥的，因为对于特定细胞类型中的给定阳离子复合物，可能有不止一种进入机制起作用。具体而言，观察到的导入现象最好用细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）的分布和摄取来解释，例如多配体蛋白聚糖和磷脂酰肌醇蛋白聚糖，除了阳离子聚合物外，它们还被证明能介导许多配体的摄取。本文简要概述了HSPG在配体内化中的作用，以及基于这些细胞表面标志物已知特性的机制假说。确定和研究硫酸乙酰肝素的糖胺聚糖和核心蛋白与PTD和阳离子聚合物之间的相互作用，对于确定细胞对它们的摄取至关重要。
