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A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes

Exosomes are small extracellular vesicles of ∼30 to 150 nm that are secreted by all cells, abundant in all biofluids, and play important roles in health and disease. However, details about the mechanism of exosome biogenesis are unclear. Here, we carried out a cargo-based analysis of exosome cargo p...

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Autores principales: Fordjour, Francis K., Guo, Chenxu, Ai, Yiwei, Daaboul, George G., Gould, Stephen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9512851/
https://www.ncbi.nlm.nih.gov/pubmed/35988652
http://dx.doi.org/10.1016/j.jbc.2022.102394
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author Fordjour, Francis K.
Guo, Chenxu
Ai, Yiwei
Daaboul, George G.
Gould, Stephen J.
author_facet Fordjour, Francis K.
Guo, Chenxu
Ai, Yiwei
Daaboul, George G.
Gould, Stephen J.
author_sort Fordjour, Francis K.
collection PubMed
description Exosomes are small extracellular vesicles of ∼30 to 150 nm that are secreted by all cells, abundant in all biofluids, and play important roles in health and disease. However, details about the mechanism of exosome biogenesis are unclear. Here, we carried out a cargo-based analysis of exosome cargo protein biogenesis in which we identified the most highly enriched exosomal cargo proteins and then followed their biogenesis, trafficking, and exosomal secretion to test different hypotheses for how cells make exosomes. We show that exosome cargo proteins bud from cells (i) in exosome-sized vesicles regardless of whether they are localized to plasma or endosome membranes, (ii) ∼5-fold more efficiently when localized to the plasma membrane, (iii) ∼5-fold less efficiently when targeted to the endosome membrane, (iv) by a stochastic process that leads to ∼100-fold differences in their abundance from one exosome to another, and (v) independently of small GTPase Rab27a, the ESCRT complex–associated protein Alix, or the cargo protein CD63. Taken together, our results demonstrate that cells use a shared, stochastic mechanism to bud exosome cargoes along the spectrum of plasma and endosome membranes and far more efficiently from the plasma membrane than the endosome. Our observations also indicate that the pronounced variation in content between different exosome-sized vesicles is an inevitable consequence of a stochastic mechanism of small vesicle biogenesis, that the origin membrane of exosome-sized extracellular vesicles simply cannot be determined, and that most of what we currently know about exosomes has likely come from studies of plasma membrane-derived vesicles.
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spelling pubmed-95128512022-09-30 A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes Fordjour, Francis K. Guo, Chenxu Ai, Yiwei Daaboul, George G. Gould, Stephen J. J Biol Chem Research Article Exosomes are small extracellular vesicles of ∼30 to 150 nm that are secreted by all cells, abundant in all biofluids, and play important roles in health and disease. However, details about the mechanism of exosome biogenesis are unclear. Here, we carried out a cargo-based analysis of exosome cargo protein biogenesis in which we identified the most highly enriched exosomal cargo proteins and then followed their biogenesis, trafficking, and exosomal secretion to test different hypotheses for how cells make exosomes. We show that exosome cargo proteins bud from cells (i) in exosome-sized vesicles regardless of whether they are localized to plasma or endosome membranes, (ii) ∼5-fold more efficiently when localized to the plasma membrane, (iii) ∼5-fold less efficiently when targeted to the endosome membrane, (iv) by a stochastic process that leads to ∼100-fold differences in their abundance from one exosome to another, and (v) independently of small GTPase Rab27a, the ESCRT complex–associated protein Alix, or the cargo protein CD63. Taken together, our results demonstrate that cells use a shared, stochastic mechanism to bud exosome cargoes along the spectrum of plasma and endosome membranes and far more efficiently from the plasma membrane than the endosome. Our observations also indicate that the pronounced variation in content between different exosome-sized vesicles is an inevitable consequence of a stochastic mechanism of small vesicle biogenesis, that the origin membrane of exosome-sized extracellular vesicles simply cannot be determined, and that most of what we currently know about exosomes has likely come from studies of plasma membrane-derived vesicles. American Society for Biochemistry and Molecular Biology 2022-08-18 /pmc/articles/PMC9512851/ /pubmed/35988652 http://dx.doi.org/10.1016/j.jbc.2022.102394 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Fordjour, Francis K.
Guo, Chenxu
Ai, Yiwei
Daaboul, George G.
Gould, Stephen J.
A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes
title A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes
title_full A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes
title_fullStr A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes
title_full_unstemmed A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes
title_short A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes
title_sort shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9512851/
https://www.ncbi.nlm.nih.gov/pubmed/35988652
http://dx.doi.org/10.1016/j.jbc.2022.102394
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