文章基本信息

标题：Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production
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作者：Chen-Yi Wu ; Jhih-Gang Jhang ; Wan-Syuan Lin 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：12
页码：1-18
DOI：10.1016/j.isci.2021.103437
语种：English
出版社：Elsevier
摘要：SummaryExosomes are important for cell–cell communication. Deficiencies in the human dihydroceramide desaturase gene,DEGS1, increase the dihydroceramide-to-ceramide ratio and cause hypomyelinating leukodystrophy. However, the disease mechanism remains unknown. Here, we developed anin vivoassay with spatially controlled expression of exosome markers inDrosophilaeye imaginal discs and showed that the level and activity of the DEGS1 ortholog, Ifc, correlated with exosome production. Knocking outifcdecreased the density of the exosome precursor intraluminal vesicles (ILVs) in the multivesicular endosomes (MVEs) and reduced the number of exosomes released. Whileifcoverexpression and autophagy inhibition both enhanced exosome production, combining the two had no additive effect. Moreover, DEGS1 activity was sufficient to drive ILV formationin vitro. Together, DEGS1/Ifc controls the dihydroceramide-to-ceramide ratio and enhances exosome secretion by promoting ILV formation and preventing the autophagic degradation of MVEs. These findings provide a potential cause for the neuropathy associated with DEGS1-deficient mutations.Graphical abstractDisplay OmittedHighlights•Anin vivosystem was developed for observing exosome production inDrosophila•Dihydroceramide desaturase (DEGS1/Ifc) promotes exosome production at two steps•DEGS1/Ifc drives membrane invagination for the formation of intraluminal vesicles•DEGS1/Ifc inhibits autophagic degradation of MVEs and increases exosome releaseCell biology; Functional aspects of cell biology