Impact of the endosomal escape activity of cell-penetrating peptides on the endocytic pathway

作者：H. Kondow-McConaghy, Nandhini Muthukrishnan, Alfredo Erazo-Oliveras, Kristina Najjar, R. Juliano, Jean-Philippe Pellois · 发表于：ACS Chemical Biology · 年份：2020 · DOI：10.1021/acschembio.0c00319 · 被引用次数：36 · 研究领域：Chemistry、Medicine

Cell-penetrating peptides (CPPs) are routinely used for the delivery of macromolecules into live human cells. To enter the cytosolic space of cells, CPPs typically permeabilize the membrane of endosomes. In turn, several approaches have been developed to increase the endosomal membrane permeation activity of CPPs so as to improve delivery efficiencies. The endocytic pathway is however important in maintaining cellular homeostasis and understanding how endosomal permeation impacts cells is now critical to define the general utility of CPPs. Herein, we investigate how CPP-based delivery protocols affect the endocytic network. We detect that in some cases, cell penetration induces the activation of Chmp1b, Galectin-3, and TFEB, components of endosomal repair, organelle clearance, and biogenesis pathways, respectively. We also detect that cellular delivery modulates endocytosis and endocytic proteolysis. Remarkably, a multimeric analog of the prototypical CPP TAT permeabilizes endosomes efficiently without inducing membrane damage responses. These results challenge the notion that reagents that make endosomes leaky are generally toxic. Instead, our data indicates that it is possible to enter cells with minimal deleterious effects.