Mechanism of Cell Penetration by Permeabilization of Late Endosomes: Interplay between a Multivalent TAT Peptide and Bis(monoacylglycero)phosphate.
Mechanism of Cell Penetration by Permeabilization of Late Endosomes: Interplay between a Multivalent TAT Peptide and Bis(monoacylglycero)phosphate.
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DOI：
10.1016/j.chembiol.2020.07.015
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发表时间：
2020-10-15
影响因子：
8.6
通讯作者：
Pellois JP
中科院分区：
文献类型：
--
作者：
Brock DJ;Kondow-McConaghy H;Allen J;Brkljača Z;Kustigian L;Jiang M;Zhang J;Rye H;Vazdar M;Pellois JP
许多细胞递送试剂通过逃离内吞细胞器（更具体地，晚期内体）的腔而进入细胞的胞质空间。内体膜渗透的机制仍不清楚，这阻碍了递送剂的改进。在这里，我们研究如何3TAT，一个分支的类似物的细胞穿透肽（CPP）达特，实现透化的双层含有双（单酰甘油）磷酸盐（BMP），脂质中发现的晚期内体。我们确定该肽不会诱导单个脂质双层的渗漏。相反，泄漏需要膜之间的接触。肽驱动的双层接触导致融合，脂质混合，以及关键的是，近端双层内的肽封装。值得注意的是，这种包封是BMP的独特性质，其解释了CPP的膜渗漏活性的特异性。因此，这些结果支持细胞渗透的模型，需要BMP和双层之间的附近，两个独特的BMP丰富和多泡晚期内体的功能。内体膜易位需要在紧密接触的双层之间包封阳离子CPP。阴离子脂质BMP的存在和丰度是腔漏的主要决定因素。分子动力学模拟通过肽诱导的BMP空间无序和反胶束形成解释了这一机制。
Many cellular delivery reagents enter the cytosolic space of cells by escaping the lumen of endocytic organelles and, more specifically, late endosomes. The mechanisms involved in endosomal membrane permeation remain largely unresolved, which impedes the improvement of delivery agents. Herein, we investigate how 3TAT, a branched analog of the cell-penetrating peptide (CPP) TAT, achieves the permeabilization of bilayers containing bis(monoacylglycerol)phosphate (BMP), a lipid found in late endosomes. We establish that the peptide does not induce the leakage of individual lipid bilayers. Instead, leakage requires contact between membranes. Peptide-driven bilayer contacts lead to fusion, lipid mixing, and, critically, peptide encapsulation within proximal bilayers. Notably, this encapsulation is a distinctive property of BMP that explains the specificity of the CPP’s membrane leakage activity. These results therefore support a model of cell penetration that requires both BMP and the vicinity between bilayers, two features unique to BMP-rich and multivesicular late endosomes. Endosomal membrane translocation requires encapsulation of cationic CPPs between bilayers brought into close contact. The presence and abundance of the anionic lipid BMP are primary determinants of luminal leakage. Molecular dynamic simulations explain this mechanism through peptide-induced BMP spatial disarrangement and inverted micelle formation.
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