Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production
Chen-Yi Wu,
Jhih-Gang Jhang,
Wan-Syuan Lin,
Pei-Huan Chuang,
Chih-Wei Lin,
Li-An Chu,
Ann-Shyn Chiang,
Han-Chen Ho,
Chih-Chiang Chan,
Shu-Yi Huang
Affiliations
Chen-Yi Wu
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei City 100233, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei City 100225, Taiwan
Jhih-Gang Jhang
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei City 100233, Taiwan
Wan-Syuan Lin
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei City 100233, Taiwan
Pei-Huan Chuang
Department of Medical Research, National Taiwan University Hospital, Taipei City 100225, Taiwan
Chih-Wei Lin
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei City 100233, Taiwan
Li-An Chu
Brain Research Center, National Tsing Hua University, Hsinchu 30013, Taiwan; Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
Ann-Shyn Chiang
Brain Research Center, National Tsing Hua University, Hsinchu 30013, Taiwan; Institute of Systems Neuroscience, National Tsing Hua University, Hsinchu 30013, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung 40402, Taiwan; Kavli Institute for Brain and Mind, University of California at San Diego, La Jolla, CA 92093-0115, USA
Han-Chen Ho
Department of Anatomy, Tzu Chi University, Hualien 97004, Taiwan
Chih-Chiang Chan
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei City 100233, Taiwan; Corresponding author
Shu-Yi Huang
Department of Medical Research, National Taiwan University Hospital, Taipei City 100225, Taiwan; Corresponding author
Summary: Exosomes 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 an in vivo assay with spatially controlled expression of exosome markers in Drosophila eye imaginal discs and showed that the level and activity of the DEGS1 ortholog, Ifc, correlated with exosome production. Knocking out ifc decreased the density of the exosome precursor intraluminal vesicles (ILVs) in the multivesicular endosomes (MVEs) and reduced the number of exosomes released. While ifc overexpression and autophagy inhibition both enhanced exosome production, combining the two had no additive effect. Moreover, DEGS1 activity was sufficient to drive ILV formation in 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.
