Fatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide

Summary: Delivering peptides into cells could open up possibilities for targeting intracellular proteins. Although fatty acylation of peptide therapeutics improves their systemic half-life, it remains unclear how it influences their cellular uptake. Here, we demonstrate that a fatty acylated peptide...

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Autores principales:	Xinxin Gao, Ann De Mazière, Rhiannon Beard, Judith Klumperman, Rami N. Hannoush
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Biological sciences Biochemistry Biochemical engineering Biotechnology Science Q
Acceso en línea:	https://doaj.org/article/287ac2a1e17845f6811e652189cbfe08
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spelling	oai:doaj.org-article:287ac2a1e17845f6811e652189cbfe082021-11-20T05:08:24ZFatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide2589-004210.1016/j.isci.2021.103220https://doaj.org/article/287ac2a1e17845f6811e652189cbfe082021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221011883https://doaj.org/toc/2589-0042Summary: Delivering peptides into cells could open up possibilities for targeting intracellular proteins. Although fatty acylation of peptide therapeutics improves their systemic half-life, it remains unclear how it influences their cellular uptake. Here, we demonstrate that a fatty acylated peptide exhibits enhanced cellular internalization and cytosolic distribution compared to the un-acylated version. By using a cystine-knot peptide as a model system, we report an efficient strategy for site-specific conjugation of fatty acids. Peptides modified with fatty acids of different chain lengths entered cells through clathrin-mediated and macropinocytosis pathways. The cellular uptake was mediated by the length of the hydrocarbon chain, with myristic acid conjugates displaying the highest distribution across the cytoplasm including the cytosol, and endomembranes of the ER, Golgi and mitochondria. Our studies demonstrate how fatty acylation improves the cellular uptake of peptides, and lay the groundwork for future development of bioactive peptides with enhanced intracellular distribution.Xinxin GaoAnn De MazièreRhiannon BeardJudith KlumpermanRami N. HannoushElsevierarticleBiological sciencesBiochemistryBiochemical engineeringBiotechnologyScienceQENiScience, Vol 24, Iss 11, Pp 103220- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biological sciences Biochemistry Biochemical engineering Biotechnology Science Q
spellingShingle	Biological sciences Biochemistry Biochemical engineering Biotechnology Science Q Xinxin Gao Ann De Mazière Rhiannon Beard Judith Klumperman Rami N. Hannoush Fatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide
description	Summary: Delivering peptides into cells could open up possibilities for targeting intracellular proteins. Although fatty acylation of peptide therapeutics improves their systemic half-life, it remains unclear how it influences their cellular uptake. Here, we demonstrate that a fatty acylated peptide exhibits enhanced cellular internalization and cytosolic distribution compared to the un-acylated version. By using a cystine-knot peptide as a model system, we report an efficient strategy for site-specific conjugation of fatty acids. Peptides modified with fatty acids of different chain lengths entered cells through clathrin-mediated and macropinocytosis pathways. The cellular uptake was mediated by the length of the hydrocarbon chain, with myristic acid conjugates displaying the highest distribution across the cytoplasm including the cytosol, and endomembranes of the ER, Golgi and mitochondria. Our studies demonstrate how fatty acylation improves the cellular uptake of peptides, and lay the groundwork for future development of bioactive peptides with enhanced intracellular distribution.
format	article
author	Xinxin Gao Ann De Mazière Rhiannon Beard Judith Klumperman Rami N. Hannoush
author_facet	Xinxin Gao Ann De Mazière Rhiannon Beard Judith Klumperman Rami N. Hannoush
author_sort	Xinxin Gao
title	Fatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide
title_short	Fatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide
title_full	Fatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide
title_fullStr	Fatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide
title_full_unstemmed	Fatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide
title_sort	fatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/287ac2a1e17845f6811e652189cbfe08
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Fatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide

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