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Mol Ther. 2018 Feb 7;26(2):648-658. doi: 10.1016/j.ymthe.2017.11.020. Epub 2018 Jan 6.

Cellular Uptake of A Taurine-Modified, Ester Bond-Decorated D-Peptide Derivative via Dynamin-Based Endocytosis and Macropinocytosis.

Author information

1
Department of Chemistry, Brandeis University, 415 South St., Waltham, MA 02453, USA.
2
Department of Biology, Brandeis University, 415 South St., Waltham, MA 02453, USA.
3
Department of Biology, Brandeis University, 415 South St., Waltham, MA 02453, USA; Departments of Cell Biology and Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
Department of Chemistry, Brandeis University, 415 South St., Waltham, MA 02453, USA. Electronic address: bxu@brandeis.edu.

Abstract

Most of the peptides used for promoting cellular uptake bear positive charges. In our previous study, we reported an example of taurine (bearing negative charges in physiological conditions) promoting cellular uptake of D-peptides. Taurine, conjugated to a small D-peptide via an ester bond, promotes the cellular uptake of this D-peptide. Particularly, intracellular carboxylesterase (CES) instructs the D-peptide to self-assemble and to form nanofibers, which largely disfavors efflux and further enhances the intracellular accumulation of the D-peptide, as supported by that the addition of CES inhibitors partially impaired cellular uptake of this molecule in mammalian cell lines. Using dynamin 1, 2, and 3 triple knockout (TKO) mouse fibroblasts, we demonstrated that cells took up this molecule via macropinocytosis and dynamin-dependent endocytosis. Imaging of Drosophila larval blood cells derived from endocytic mutants confirmed the involvement of multiple endocytosis pathways. Electron microscopy (EM) indicated that the precursors can form aggregates on the cell surface to facilitate the cellular uptake via macropinocytosis. EM also revealed significantly increased numbers of vesicles in the cytosol. This work provides new insights into the cellular uptake of taurine derivative for intracellular delivery and self-assembly of D-peptides.

KEYWORDS:

TEM; endocytosis; enzymes; esterase; macropinocytosis; peptides; self-assembly; taurine

PMID:
29396265
PMCID:
PMC5835119
DOI:
10.1016/j.ymthe.2017.11.020
[Indexed for MEDLINE]
Free PMC Article

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