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

Jie Zhou, Xuewen Du, Cristina Berciu, Steven J. Del Signore, Xiaoyi Chen, Natsuko Yamagata, Avital A. Rodal, Daniela Nicastro, Bing Xu

Research output: Contribution to journalArticle

2 Citations (Scopus)

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. Zhou et al. demonstrate that taurine, conjugated to a small D-peptide via an ester bond, promotes the cellular uptake of this D-peptide via multiple endocytosis pathways for intracellular carboxylesterase (CES)-instructed self-assembly, which largely disfavors efflux and further enhances the intracellular accumulation of the D-peptide.

Original languageEnglish (US)
Pages (from-to)648-658
Number of pages11
JournalMolecular Therapy
Volume26
Issue number2
DOIs
StatePublished - Feb 7 2018

Fingerprint

Dynamins
Taurine
Endocytosis
Esters
Peptides
Carboxylesterase
Dynamin III
Electron Microscopy
Dynamin I
Dynamin II
Nanofibers
Knockout Mice
Cytosol
Drosophila
Blood Cells
Fibroblasts

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Cellular Uptake of A Taurine-Modified, Ester Bond-Decorated D-Peptide Derivative via Dynamin-Based Endocytosis and Macropinocytosis. / Zhou, Jie; Du, Xuewen; Berciu, Cristina; Del Signore, Steven J.; Chen, Xiaoyi; Yamagata, Natsuko; Rodal, Avital A.; Nicastro, Daniela; Xu, Bing.

In: Molecular Therapy, Vol. 26, No. 2, 07.02.2018, p. 648-658.

Research output: Contribution to journalArticle

Zhou, Jie ; Du, Xuewen ; Berciu, Cristina ; Del Signore, Steven J. ; Chen, Xiaoyi ; Yamagata, Natsuko ; Rodal, Avital A. ; Nicastro, Daniela ; Xu, Bing. / Cellular Uptake of A Taurine-Modified, Ester Bond-Decorated D-Peptide Derivative via Dynamin-Based Endocytosis and Macropinocytosis. In: Molecular Therapy. 2018 ; Vol. 26, No. 2. pp. 648-658.
@article{fa8874f2efa54000951d915fce2a615d,
title = "Cellular Uptake of A Taurine-Modified, Ester Bond-Decorated D-Peptide Derivative via Dynamin-Based Endocytosis and Macropinocytosis",
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. Zhou et al. demonstrate that taurine, conjugated to a small D-peptide via an ester bond, promotes the cellular uptake of this D-peptide via multiple endocytosis pathways for intracellular carboxylesterase (CES)-instructed self-assembly, which largely disfavors efflux and further enhances the intracellular accumulation of the D-peptide.",
keywords = "endocytosis, enzymes, esterase, macropinocytosis, peptides, self-assembly, taurine, TEM",
author = "Jie Zhou and Xuewen Du and Cristina Berciu and {Del Signore}, {Steven J.} and Xiaoyi Chen and Natsuko Yamagata and Rodal, {Avital A.} and Daniela Nicastro and Bing Xu",
year = "2018",
month = "2",
day = "7",
doi = "10.1016/j.ymthe.2017.11.020",
language = "English (US)",
volume = "26",
pages = "648--658",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Cellular Uptake of A Taurine-Modified, Ester Bond-Decorated D-Peptide Derivative via Dynamin-Based Endocytosis and Macropinocytosis

AU - Zhou, Jie

AU - Du, Xuewen

AU - Berciu, Cristina

AU - Del Signore, Steven J.

AU - Chen, Xiaoyi

AU - Yamagata, Natsuko

AU - Rodal, Avital A.

AU - Nicastro, Daniela

AU - Xu, Bing

PY - 2018/2/7

Y1 - 2018/2/7

N2 - 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. Zhou et al. demonstrate that taurine, conjugated to a small D-peptide via an ester bond, promotes the cellular uptake of this D-peptide via multiple endocytosis pathways for intracellular carboxylesterase (CES)-instructed self-assembly, which largely disfavors efflux and further enhances the intracellular accumulation of the D-peptide.

AB - 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. Zhou et al. demonstrate that taurine, conjugated to a small D-peptide via an ester bond, promotes the cellular uptake of this D-peptide via multiple endocytosis pathways for intracellular carboxylesterase (CES)-instructed self-assembly, which largely disfavors efflux and further enhances the intracellular accumulation of the D-peptide.

KW - endocytosis

KW - enzymes

KW - esterase

KW - macropinocytosis

KW - peptides

KW - self-assembly

KW - taurine

KW - TEM

UR - http://www.scopus.com/inward/record.url?scp=85041109934&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041109934&partnerID=8YFLogxK

U2 - 10.1016/j.ymthe.2017.11.020

DO - 10.1016/j.ymthe.2017.11.020

M3 - Article

C2 - 29396265

AN - SCOPUS:85041109934

VL - 26

SP - 648

EP - 658

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 2

ER -