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Theranostics 2016; 6(12):2099-2113. doi:10.7150/thno.16587 This issue Cite

Research Paper

Intracellular Trafficking Network of Protein Nanocapsules: Endocytosis, Exocytosis and Autophagy

Jinxie Zhang^1,2,*, Xudong Zhang ^1,2,3,*✉, Gan Liu^1,2,*, Danfeng Chang^1,2, Xin Liang^{2, 4}, Xianbing Zhu^1,2, Wei Tao^1,2, Lin Mei^{1, 2✉}

1. School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China;
2. Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, P.R. China;
3. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695, USA;
4. Department of Pharmacological and Physiological Science and Center for Neuroscience, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
* These authors contributed equally to this work.

✉ Corresponding authors: Lin Mei: Tel/Fax: +86 75526036736, E-mail: mei.lintsinghua.edu.cn. Xudong Zhang: Tel/Fax: +1(314) 882-9360, E-mail: xzhang60edu

Abstract

The inner membrane vesicle system is a complex transport system that includes endocytosis, exocytosis and autophagy. However, the details of the intracellular trafficking pathway of nanoparticles in cells have been poorly investigated. Here, we investigate in detail the intracellular trafficking pathway of protein nanocapsules using more than 30 Rab proteins as markers of multiple trafficking vesicles in endocytosis, exocytosis and autophagy. We observed that FITC-labeled protein nanoparticles were internalized by the cells mainly through Arf6-dependent endocytosis and Rab34-mediated micropinocytosis. In addition to this classic pathway: early endosome (EEs)/late endosome (LEs) to lysosome, we identified two novel transport pathways: micropinocytosis (Rab34 positive)-LEs (Rab7 positive)-lysosome pathway and EEs-liposome (Rab18 positive)-lysosome pathway. Moreover, the cells use slow endocytosis recycling pathway (Rab11 and Rab35 positive vesicles) and GLUT4 exocytosis vesicles (Rab8 and Rab10 positive) transport the protein nanocapsules out of the cells. In addition, protein nanoparticles are observed in autophagosomes, which receive protein nanocapsules through multiple endocytosis vesicles. Using autophagy inhibitor to block these transport pathways could prevent the degradation of nanoparticles through lysosomes. Using Rab proteins as vesicle markers to investigation the detail intracellular trafficking of the protein nanocapsules, will provide new targets to interfere the cellular behaver of the nanoparticles, and improve the therapeutic effect of nanomedicine.

Keywords: Nanomedicine, Endocytosis, Autophagy, Exocytosis, Protein nanocapsules.

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