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Updated: Aug 28, 2025

Author Spotlight: Regulation and Dysregulation of ER-Mitochondria Contacts — Implications for Neurodegenerative Disease Pathogenesis
Published on: October 11, 2024
ER membrane contact sites support endosomal small GTPase conversion for exosome secretion
Frederik J Verweij1,2,3, Maarten P Bebelman1,4,5, Anna E George2,3
1Institute for Psychiatry and Neurosciences of Paris, Hopital Saint-Anne, Université de Paris, Institut national de la santé et de la recherche médicale, U1266, Paris, France.
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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