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

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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Cell biology Functional aspects of cell biology Science Q
Acceso en línea:	https://doaj.org/article/d55d5ad4e81547aca45b87af80fcaba8
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spelling	oai:doaj.org-article:d55d5ad4e81547aca45b87af80fcaba82021-11-28T04:36:23ZDihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production2589-004210.1016/j.isci.2021.103437https://doaj.org/article/d55d5ad4e81547aca45b87af80fcaba82021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221014085https://doaj.org/toc/2589-0042Summary: 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.Chen-Yi WuJhih-Gang JhangWan-Syuan LinPei-Huan ChuangChih-Wei LinLi-An ChuAnn-Shyn ChiangHan-Chen HoChih-Chiang ChanShu-Yi HuangElsevierarticleCell biologyFunctional aspects of cell biologyScienceQENiScience, Vol 24, Iss 12, Pp 103437- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cell biology Functional aspects of cell biology Science Q
spellingShingle	Cell biology Functional aspects of cell biology Science Q 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 Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production
description	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.
format	article
author	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
author_facet	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
author_sort	Chen-Yi Wu
title	Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production
title_short	Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production
title_full	Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production
title_fullStr	Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production
title_full_unstemmed	Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production
title_sort	dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/d55d5ad4e81547aca45b87af80fcaba8
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Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production

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