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

iScience (Dec 2021)

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

Journal volume & issue: Vol. 24, no. 12
p. 103437

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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