Oxidative Stress Triggers Ca2+-Dependent Lysosome Trafficking and Activation of Acid Sphingomyelinase

Cellular Physiology and Biochemistry

关键词: Ceramide;    Lysosomes;    Acid sphingomyelinase;    Vesicle;    Fusion;   

DOI  :  10.1159/000341460

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Recent studies demonstrate that rapid translocation of the acid sphingomyelinase (ASM), a lysosomal hydrolase, to the outer leaflet of the cell membrane and concomitant release of ceramide constitute a common cellular signaling cascade to various stimuli including CD95 ligation, UV-irradiation, bacterial and viral infections. Reactive oxygen species (ROS) were shown to play a crucial role in regulating this signaling cascade at least for some bacterial infections and UV-irradiation. However, the precise role of ROS for regulation of ASM is unknown. Here, by confocal microscopy and flow cytometry analysis, we demonstrate that hydrogen peroxide (H₂O₂), a primary form of ROS in mammalian cells, induces very rapid translocation of ASM and formation of ceramide-enriched membrane platforms in the plasma membrane of Jurkat T cells. In parallel, H₂O₂ triggers lysosome trafficking and fusion with the plasma membrane, i.e. lysosome exocytosis, as detected by exposure of a lysosome-associated protein, LAMP1. Depletion of intracellular Ca²⁺ by cell permeable EGTA-AM inhibits H₂O₂-induced lysosome exocytosis, ASM translocation and formation of ceramide-enriched platforms. Pharmacological inhibition or genetic deficiency of ASM did not affect H₂O₂-induced lysosome exocytosis. These results indicate that ROS-induced membrane translocation of ASM is mediated by exocytosis of lysosomes, which is dependent on intracellular Ca²⁺ release.

【 授权许可】

CC BY-NC-ND