Wu Chen-Yi, Jhang Jhih-Gang, Lin Wan-Syuan, Chuang Pei-Huan, Lin Chih-Wei, Chu Li-An, Chiang Ann-Shyn, Ho Han-Chen, Chan Chih-Chiang, Huang Shu-Yi
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.
iScience. 2021 Nov 14;24(12):103437. doi: 10.1016/j.isci.2021.103437. eCollection 2021 Dec 17.
Exosomes are important for cell-cell communication. Deficiencies in the human dihydroceramide desaturase gene, , increase the dihydroceramide-to-ceramide ratio and cause hypomyelinating leukodystrophy. However, the disease mechanism remains unknown. Here, we developed an assay with spatially controlled expression of exosome markers in eye imaginal discs and showed that the level and activity of the DEGS1 ortholog, Ifc, correlated with exosome production. Knocking out decreased the density of the exosome precursor intraluminal vesicles (ILVs) in the multivesicular endosomes (MVEs) and reduced the number of exosomes released. While overexpression and autophagy inhibition both enhanced exosome production, combining the two had no additive effect. Moreover, DEGS1 activity was sufficient to drive ILV formation . 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.
外泌体对细胞间通讯很重要。人类二氢神经酰胺去饱和酶基因（DEGS1）的缺陷会增加二氢神经酰胺与神经酰胺的比例，并导致低髓鞘性脑白质营养不良。然而，该疾病的机制仍然未知。在这里，我们开发了一种在果蝇眼成虫盘中外泌体标记物空间控制表达的检测方法，并表明DEGS1的直系同源物Ifc的水平和活性与外泌体产生相关。敲除Ifc会降低多泡体（MVE）中外泌体前体腔内小泡（ILV）的密度，并减少释放的外泌体数量。虽然Ifc过表达和自噬抑制都增强了外泌体产生，但两者结合没有叠加效应。此外，DEGS1活性足以驱动ILV形成。总之，DEGS1/Ifc通过促进ILV形成和防止MVE的自噬降解来控制二氢神经酰胺与神经酰胺的比例，并增强外泌体分泌。这些发现为与DEGS1缺陷突变相关的神经病变提供了一个潜在原因。
