CD63, a new therapeutical candidate for cholesterol homeostasis regulation through extracellular vesicles?

Abstract

CD63 is a tetraspanin initially associated with late endosomes and contributes to numerous functions at the cell level, such as intracellular endosomal and lysosomal trafficking, adhesion, and motility. CD63 also plays a key role in the biogenesis and release of exosomes, i.e., small extracellular vesicles (EVs) of endosomal origin, facilitating the formation of multivesicular bodies (MVBs), the coordination with the endosomal sorting complexes required for transport (ESCRT) machinery, the selection of cargoes carried by future exosomes, and the fusion of MVBs with the plasma membrane for exosome release. In a recent publication in Nature Cell Biology, Guillaume van Niel’s team provides arguments in favor of another EV-linked function for CD63, namely the regulation of cholesterol storage and release by small EVs of endogenous origin. Complemented by two other publications from the teams of Keisuke Ito and Xabier Ostreikoetxea, which respectively describe the role of (i) mitochondrial metabolism on CD63 function and (ii) the link between the reduced CD63⁺ small EVs and dyslipidemia, these arguments highlight the key role of CD63 in the regulation of cholesterol homeostasis through exosomes and more widely small EVs in physiological and pathological conditions. Future research on CD63 may thus redefine our approach to cellular lipid management and therapeutic lipid delivery.

Keywords

Extracellular vesicles / exosomes / CD63 / cholesterol balance / endosomes

References

[1] Charrin S,Boucheix C.Tetraspanins at a glance.J Cell Sci2014;127:3641-8

[2] Lang T.Tetraspanins.Curr Biol2020;30:R204-6

[3] Andreu Z.Tetraspanins in extracellular vesicle formation and function.Front Immunol2014;5:442 PMCID:PMC4165315

[4] Toribio V.Tetraspanins interweave EV secretion, endosomal network dynamics and cellular metabolism.Eur J Cell Biol2022;101:151229

[5] Pfrieger FW.Cholesterol and the journey of extracellular vesicles.J Lipid Res2018;59:2255-61 PMCID:PMC6277151

[6] Raposo G.Extracellular vesicles: exosomes, microvesicles, and friends.J Cell Biol2013;200:373-83 PMCID:PMC3575529

[7] Broadbent LM,Simms J.Classifying tetraspanins: a universal system for numbering residues and a proposal for naming structural motifs and subfamilies.Biochim Biophys Acta Biomembr2024;1866:184265

[8] Yáñez-Mó M,Gordon-Alonso M,Sánchez-Madrid F.Tetraspanin-enriched microdomains: a functional unit in cell plasma membranes.Trends Cell Biol2009;19:434-46

[9] Escola JM,Stoorvogel W,Yoshie O.Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes.J Biol Chem1998;273:20121-7

[10] Palmulli R,Piontek MC.CD63 sorts cholesterol into endosomes for storage and distribution via exosomes.Nat Cell Biol2024;26:1093-109

[11] Zimmerman B,McMillan BJ.Crystal structure of a full-length human tetraspanin reveals a cholesterol-binding pocket.Cell2016;167:1041-51.e11 PMCID:PMC5127602

[12] Höglinger D,Sanchez-Heras E.NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress.Nat Commun2019;10:4276 PMCID:PMC6753064

[13] Lu A.Endolysosomal cholesterol export: more than just NPC1.Bioessays2022;44:e2200111

[14] Strauss K,Runz H.Exosome secretion ameliorates lysosomal storage of cholesterol in Niemann-Pick type C disease.J Biol Chem2010;285:26279-88 PMCID:PMC2924046

[15] Vance JE.Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin.J Lipid Res2014;55:1609-21 PMCID:PMC4109756

[16] Kestecher BM,Ghosal S.Reduced circulating CD63⁺ extracellular vesicle levels associate with atherosclerosis in hypercholesterolaemic mice and humans.Cardiovasc Diabetol2024;23:368 PMCID:PMC11487797

[17] Bonora M,van Gastel N.A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.Cell Stem Cell2024;31:359-77.e10 PMCID:PMC10957094

[18] Farooqi IS.Translational potential of mouse models of human metabolic disease.Cell2024;187:4129-43

[19] Buffolo F,Camussi G.Role of extracellular vesicles in the pathogenesis of vascular damage.Hypertension2022;79:863-73 PMCID:PMC9010370

[20] Cai J,Tan X.SRY gene transferred by extracellular vesicles accelerates atherosclerosis by promotion of leucocyte adherence to endothelial cells.Clin Sci2015;129:259-69

[21] Chen L,Li Q,Li H.Exosome-encapsulated miR-505 from ox-LDL-treated vascular endothelial cells aggravates atherosclerosis by inducing NET formation.Acta Biochim Biophys Sin2019;51:1233-41