2. Academic Validation
  3. ADAM Sheddase Activity Promotes the Detachment of Small Extracellular Vesicles From the Plasma Membrane

ADAM Sheddase Activity Promotes the Detachment of Small Extracellular Vesicles From the Plasma Membrane

  • J Extracell Vesicles. 2025 Jul;14(7):e70114. doi: 10.1002/jev2.70114.
Chloé Bizingre 1 2,  Zaira Arellano-Anaya 1 2,  Flavien Picard 3,  Mathéa Pietri 1 2 3,  Anne Baudry 1 2 3,  Florence Roussel 3,  Clara Bianchi 1 2 3,  Aurélie Alleaume-Butaux 1 2 3,  Hector Ardila-Osorio 1 2,  Maryse Romao 4,  Grégory Lavieu 5,  Graça Raposo 4,  Benoit Schneider 1 2 3
Affiliations

Affiliations

  • 1 INSERM UMR-S 1124, Paris, France.
  • 2 Université Paris Cité, UMR-S 1124, Paris, France.
  • 3 Ecole Polytechnique, CNRS UMR7654, Institut Polytechnique de Paris, Palaiseau, France.
  • 4 Institut Curie, Paris Sciences et Lettres Research University, CNRS UMR144, Structure and Membrane Compartments, Paris, France.
  • 5 Université Paris Cité, INSERM ERL U 1316, CNRS UMR 7057, Paris, France.
PMID: 40673783 DOI: 10.1002/jev2.70114
Abstract

Small extracellular vesicles (SEVs) are involved in diverse functions in normal and pathological situations, including intercellular communication, immunity, metastasis and neurodegeneration. Cell release of SEVs is assumed to occur passively right after multivesicular bodies of the endocytic pathway fuse with the plasma membrane. We show here that the completion of SEV release depends on membrane-bound ADAM10 and ADAM17 sheddases that promote the detachment of SEVs from the cell surface by catalysing the cleavage of adhesion proteins of the SEV membrane. The intensity of ADAM10/17-mediated release of SEVs depends on a balanced control of 3-phosphoinositide-dependent kinase 1 (PDK1) and ERK1/2 signalling pathways converging on 90-kDa ribosomal S6 kinase-2 (RSK2), which, in turn, fine-tunes ADAM17 bioavailability and ADAM10/17 enzymatic activities at the plasma membrane, according to a mechanism that relies, at least in part, on variation of the rhomboid-like pseudoprotease iRhom2 cell surface level. By identifying a new proteolytic step involved in the basal release of SEVs, our work may help understand how the deregulation of ADAM10/17-mediated discharge of SEVs contributes to several pathological states.

Keywords

ERK1/2; PDK1; RSK2; exosomes; iRhom2; protein cleavage; signalling.

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