CD63 sorts cholesterol into endosomes for storage and distribution via exosomes

  • Nat Cell Biol. 2024 Jul;26(7):1093-1109. doi: 10.1038/s41556-024-01432-9.
Roberta Palmulli  #  1  2 ,  Mickaël Couty  #  2  3 ,  Melissa C Piontek  4 ,  Maharajah Ponnaiah  5 ,  Florent Dingli  6 ,  Frederik J Verweij  2 ,  Stéphanie Charrin  7 ,  Matteo Tantucci  2 ,  Sajitha Sasidharan  4 ,  Eric Rubinstein  7 ,  Anatol Kontush  8 ,  Damarys Loew  6 ,  Marie Lhomme  5 ,  Wouter H Roos  4 ,  Graça Raposo  1  9 ,  Guillaume van Niel  10  11  12  13
Affiliations
  • 1. Institut Curie, PSL Research University, CNRS, UMR144, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
  • 2. Institute of Psychiatry and Neuroscience of Paris (IPNP), Université de Paris, Paris, France.
  • 3. CRCI2NA, Nantes Université, Inserm UMR1307, CNRS UMR6075, Université d'Angers, Nantes, France.
  • 4. Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit Groningen, Groningen, The Netherlands.
  • 5. Foundation for Innovation in Cardiometabolism and Nutrition (IHU ICAN, ICAN OMICS and ICAN I/O), F-75013, Paris, France.
  • 6. CurieCoreTech Spectrométrie de Masse Protéomique, Institut Curie, PSL Research University, Paris, France.
  • 7. Centre d'Immunologie et des Maladies Infectieuses (CIMI), Sorbonne Université, Inserm, Paris, France.
  • 8. ICAN, National Institute for Health and Medical Research, Paris, France.
  • 9. Institut Curie, PSL Research University, CNRS, UMR144, Cell and Tissue Imaging Facility (PICT-IBiSA), 26, rue d'Ulm, 75248, Paris Cedex 05, France.
  • 10. Institut Curie, PSL Research University, CNRS, UMR144, 26 rue d'Ulm, 75248, Paris Cedex 05, France. [email protected].
  • 11. Institute of Psychiatry and Neuroscience of Paris (IPNP), Université de Paris, Paris, France. [email protected].
  • 12. CRCI2NA, Nantes Université, Inserm UMR1307, CNRS UMR6075, Université d'Angers, Nantes, France. [email protected].
  • 13. GHU-Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, Paris, France. [email protected].
  • # Contributed equally.
PMID: 38886558 DOI: 10.1038/s41556-024-01432-9
Abstract

Extracellular vesicles such as exosomes are now recognized as key players in intercellular communication. Their role is influenced by the specific repertoires of proteins and lipids, which are enriched when they are generated as intraluminal vesicles (ILVs) in multivesicular endosomes. Here we report that a key component of small extracellular vesicles, the tetraspanin CD63, sorts Cholesterol to ILVs, generating a pool that can be mobilized by the NPC1/2 complex, and exported via exosomes to recipient cells. In the absence of CD63, Cholesterol is retrieved from the endosomes by actin-dependent vesicular transport, placing CD63 and Cholesterol at the centre of a balance between inward and outward budding of endomembranes. These results establish CD63 as a lipid-sorting mechanism within endosomes, and show that ILVs and exosomes are alternative providers of Cholesterol.