Exosomes are small vesicles that are secreted from cells to dispose of undegraded materials and mediate intercellular communication. A major source of exosomes is intraluminal vesicles within multivesicular endosomes that undergo exocytic fusion with the plasma membrane. An alternative fate of multivesicular endosomes is fusion with lysosomes, resulting in degradation of the intraluminal vesicles. The factors that determine whether multivesicular endosomes fuse with the plasma membrane or with lysosomes are unknown. In this study, we show that impairment of endolysosomal fusion by disruption of a pathway involving the BLOC-one-related complex (BORC), the small GTPase ARL8, and the tethering factor HOPS increases exosome secretion by preventing the delivery of intraluminal vesicles to lysosomes. These findings demonstrate that endolysosomal fusion is a critical determinant of the amount of exosome secretion and suggest that suppression of the BORC–ARL8–HOPS pathway could be used to boost exosome yields in biotechnology applications.
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May 22 2023
Inhibition of endolysosome fusion increases exosome secretion
Ganesh Vilas Shelke
,
Ganesh Vilas Shelke
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
, Bethesda, MD, USA
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Chad D. Williamson
,
Chad D. Williamson
(Formal analysis, Investigation, Writing - review & editing)
1
Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
, Bethesda, MD, USA
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Michal Jarnik
,
Michal Jarnik
(Investigation, Methodology, Validation)
1
Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
, Bethesda, MD, USA
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Juan S. Bonifacino
(Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing)
1
Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
, Bethesda, MD, USA
Correspondence to Juan S. Bonifacino: juan.bonifacino@nih.gov
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Ganesh Vilas Shelke
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
, Bethesda, MD, USA
Chad D. Williamson
Formal analysis, Investigation, Writing - review & editing
1
Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
, Bethesda, MD, USA
Michal Jarnik
Investigation, Methodology, Validation
1
Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
, Bethesda, MD, USA
Juan S. Bonifacino
Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing
1
Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
, Bethesda, MD, USA
Correspondence to Juan S. Bonifacino: juan.bonifacino@nih.gov
Disclosures: The authors declare no competing interests exist.
Received:
September 20 2022
Revision Received:
February 04 2023
Accepted:
March 17 2023
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Award Id(s): ZIA HD001607
Funder(s):
H2020 Marie Skłodowska-Curie Actions
- Award Id(s): No 754412
Funder(s):
Swedish Society for Medical Research
This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.
2023
This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2023) 222 (6): e202209084.
Article history
Received:
September 20 2022
Revision Received:
February 04 2023
Accepted:
March 17 2023
Citation
Ganesh Vilas Shelke, Chad D. Williamson, Michal Jarnik, Juan S. Bonifacino; Inhibition of endolysosome fusion increases exosome secretion. J Cell Biol 5 June 2023; 222 (6): e202209084. doi: https://doi.org/10.1083/jcb.202209084
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