Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production

Abstract

Exosomes play important roles in the nervous system. Mutations in the human dihydroceramide desaturase gene, DEGS1, are recently linked to severe neurological disorders, but the cause remains unknown. Here, we show that Ifc is required for the morphology and function of Drosophila photoreceptor neurons and not in the surrounding glia, but the degeneration of ifc-KO eyes can be rescued by glial expression of ifc, possibly mediated by exosomes. We develop an in vivo assay using Drosophila eye imaginal discs and show that the level and activity of Ifc correlates with the detection of exosome-like vesicles. While ifc overexpression and autophagy inhibition both enhances exosome production, combining the two had no additive effect. Moreover, ifc-KO reduces the density of the exosome precursor intraluminal vesicles (ILVs) in vivo, and DEGS1 promotes ILV formation in vitro. In conclusion, dihydroceramide desaturase promotes exosome formation and prevents its autophagic degradation in the nervous system.