ER Membrane Contact Sites support endosomal small GTPase conversion for exosome secretion

Frederik Verweij; Maarten P Bebelman; Anna George; Mickael Couty; Anaïs Bécot; Roberta Palmulli; Xavier Heiligenstein; Julia Sires-Campos; Graca Raposo; Dirk Michiel Pegtel; Guillaume Van Niel

doi:10.1083/jcb.202112032

ER Membrane Contact Sites support endosomal small GTPase conversion for exosome secretion

Frederik Verweij, Maarten P Bebelman, Anna George, Mickael Couty, Anaïs Bécot, Roberta Palmulli, Xavier Heiligenstein, Julia Sires-Campos, Graca Raposo, Dirk Michiel Pegtel, Guillaume Van Niel

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Exosomes are endosome-derived extracellular vesicles involved in intercellular communication. They are generated as intraluminal vesicles within endosomal compartments that fuse with the plasma membrane (PM). The molecular events that generate secretory endosomes and lead to the release of exosomes are not well understood. We identified a subclass of non-proteolytic endosomes at prelysosomal stage as the compartment of origin of CD63 positive exosomes. These compartments undergo a Rab7a/Arl8b/Rab27a GTPase cascade to fuse with the PM. Dynamic endoplasmic reticulum (ER)-late endosome (LE) membrane contact sites (MCS) through ORP1L have the distinct capacity to modulate this process by affecting LE motility, maturation state, and small GTPase association. Thus, exosome secretion is a multi-step process regulated by GTPase switching and MCS, highlighting the ER as a new player in exosome-mediated intercellular communication.

Original language	English
Article number	e202112032
Pages (from-to)	1-18
Journal	Journal of Cell Biology
Volume	221
Issue number	12
Early online date	22 Sept 2022
DOIs	https://doi.org/10.1083/jcb.202112032
Publication status	Published - 5 Dec 2022

Bibliographical note

Funding Information:
This article was funded by a European Molecular Biology Organization grant (EMBO ALTF 1383-2014), a Fondation ARC pour la Recherche sur le Cancer fellowship (PJA 20161204808), and a Dutch Cancer Fund (KWF-YIG 12849) to F.J. Verweij, a Dutch Organizations for Scientific Research–Amsterdam Institute for Molecules, Medicines, and Systems STAR Graduate Program grant (022.005.031) and a Cancer Center Amsterdam travel grant to M.P. Bebelman, a Dutch Cancer Fund (KWF-5510) and a Cancer Center Amsterdam–VU University Medical Center grant to D.M. Pegtel, and a Fondation pour la Recherche Médicale grant (AJE20160635884) to G. van Niel and an Institut National Du Cancer grant (INCA N°2019-125 PLBIO19-059) to F.J. Verweij and G. van Niel. The Nikon Imaging Centre at In-stitut Curie is member of the French National Research Infrastructure France-BioImaging (ANR10-INBS-04). The authors declare no competing financial interests.

Publisher Copyright:
© 2022 Verweij et al.

Keywords

Biological Transport
Cell Communication
Cell Membrane/metabolism
Endoplasmic Reticulum/metabolism
Endosomes/enzymology
Exosomes/metabolism
rab GTP-Binding Proteins/metabolism

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title = "ER Membrane Contact Sites support endosomal small GTPase conversion for exosome secretion",

abstract = "Exosomes are endosome-derived extracellular vesicles involved in intercellular communication. They are generated as intraluminal vesicles within endosomal compartments that fuse with the plasma membrane (PM). The molecular events that generate secretory endosomes and lead to the release of exosomes are not well understood. We identified a subclass of non-proteolytic endosomes at prelysosomal stage as the compartment of origin of CD63 positive exosomes. These compartments undergo a Rab7a/Arl8b/Rab27a GTPase cascade to fuse with the PM. Dynamic endoplasmic reticulum (ER)-late endosome (LE) membrane contact sites (MCS) through ORP1L have the distinct capacity to modulate this process by affecting LE motility, maturation state, and small GTPase association. Thus, exosome secretion is a multi-step process regulated by GTPase switching and MCS, highlighting the ER as a new player in exosome-mediated intercellular communication.",

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note = "Funding Information: This article was funded by a European Molecular Biology Organization grant (EMBO ALTF 1383-2014), a Fondation ARC pour la Recherche sur le Cancer fellowship (PJA 20161204808), and a Dutch Cancer Fund (KWF-YIG 12849) to F.J. Verweij, a Dutch Organizations for Scientific Research–Amsterdam Institute for Molecules, Medicines, and Systems STAR Graduate Program grant (022.005.031) and a Cancer Center Amsterdam travel grant to M.P. Bebelman, a Dutch Cancer Fund (KWF-5510) and a Cancer Center Amsterdam–VU University Medical Center grant to D.M. Pegtel, and a Fondation pour la Recherche M{\'e}dicale grant (AJE20160635884) to G. van Niel and an Institut National Du Cancer grant (INCA N°2019-125 PLBIO19-059) to F.J. Verweij and G. van Niel. The Nikon Imaging Centre at In-stitut Curie is member of the French National Research Infrastructure France-BioImaging (ANR10-INBS-04). The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2022 Verweij et al.",

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doi = "10.1083/jcb.202112032",

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AU - Verweij, Frederik

AU - Bebelman, Maarten P

AU - George, Anna

AU - Couty, Mickael

AU - Bécot, Anaïs

AU - Palmulli, Roberta

AU - Heiligenstein, Xavier

AU - Sires-Campos, Julia

AU - Raposo, Graca

AU - Pegtel, Dirk Michiel

AU - Van Niel, Guillaume

N1 - Funding Information: This article was funded by a European Molecular Biology Organization grant (EMBO ALTF 1383-2014), a Fondation ARC pour la Recherche sur le Cancer fellowship (PJA 20161204808), and a Dutch Cancer Fund (KWF-YIG 12849) to F.J. Verweij, a Dutch Organizations for Scientific Research–Amsterdam Institute for Molecules, Medicines, and Systems STAR Graduate Program grant (022.005.031) and a Cancer Center Amsterdam travel grant to M.P. Bebelman, a Dutch Cancer Fund (KWF-5510) and a Cancer Center Amsterdam–VU University Medical Center grant to D.M. Pegtel, and a Fondation pour la Recherche Médicale grant (AJE20160635884) to G. van Niel and an Institut National Du Cancer grant (INCA N°2019-125 PLBIO19-059) to F.J. Verweij and G. van Niel. The Nikon Imaging Centre at In-stitut Curie is member of the French National Research Infrastructure France-BioImaging (ANR10-INBS-04). The authors declare no competing financial interests. Publisher Copyright: © 2022 Verweij et al.

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N2 - Exosomes are endosome-derived extracellular vesicles involved in intercellular communication. They are generated as intraluminal vesicles within endosomal compartments that fuse with the plasma membrane (PM). The molecular events that generate secretory endosomes and lead to the release of exosomes are not well understood. We identified a subclass of non-proteolytic endosomes at prelysosomal stage as the compartment of origin of CD63 positive exosomes. These compartments undergo a Rab7a/Arl8b/Rab27a GTPase cascade to fuse with the PM. Dynamic endoplasmic reticulum (ER)-late endosome (LE) membrane contact sites (MCS) through ORP1L have the distinct capacity to modulate this process by affecting LE motility, maturation state, and small GTPase association. Thus, exosome secretion is a multi-step process regulated by GTPase switching and MCS, highlighting the ER as a new player in exosome-mediated intercellular communication.

AB - Exosomes are endosome-derived extracellular vesicles involved in intercellular communication. They are generated as intraluminal vesicles within endosomal compartments that fuse with the plasma membrane (PM). The molecular events that generate secretory endosomes and lead to the release of exosomes are not well understood. We identified a subclass of non-proteolytic endosomes at prelysosomal stage as the compartment of origin of CD63 positive exosomes. These compartments undergo a Rab7a/Arl8b/Rab27a GTPase cascade to fuse with the PM. Dynamic endoplasmic reticulum (ER)-late endosome (LE) membrane contact sites (MCS) through ORP1L have the distinct capacity to modulate this process by affecting LE motility, maturation state, and small GTPase association. Thus, exosome secretion is a multi-step process regulated by GTPase switching and MCS, highlighting the ER as a new player in exosome-mediated intercellular communication.

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KW - Cell Communication

KW - Cell Membrane/metabolism

KW - Endoplasmic Reticulum/metabolism

KW - Endosomes/enzymology

KW - Exosomes/metabolism

KW - rab GTP-Binding Proteins/metabolism

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DO - 10.1083/jcb.202112032

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SN - 0021-9525

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EP - 18

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 12

M1 - e202112032

ER -

ER Membrane Contact Sites support endosomal small GTPase conversion for exosome secretion

Abstract

Bibliographical note

Keywords

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