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: CD63; Extracellular vesicles; cholesterol balance; endosomes; exosomes.
© The Author(s) 2025.