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Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis

2005; Rockefeller University Press; Volume: 202; Issue: 2 Linguagem: Inglês

10.1084/jem.20041685

1540-9538

Michihiko Miyaji, Zhe-Xiong Jin, Shohei Yamaoka, Ryuichi Amakawa, Shirou Fukuhara, Satoshi B. Sato, Toshihide Kobayashi, Naochika Domae, Tsuneyo Mimori, Eda T. Bloom, Toshiro Okazaki, Hisanori Umehara,

Phagocytosis and Immune Regulation

Engagement of the Fas receptor (CD95) initiates multiple signaling pathways that lead to apoptosis, such as the formation of death-inducing signaling complex (DISC), activation of caspase cascades, and the generation of the lipid messenger, ceramide. Sphingomyelin (SM) is a major component of lipid rafts, which are specialized structures that enhance the efficiency of membrane receptor signaling and are a main source of ceramide. However, the functions of SM in Fas-mediated apoptosis have yet to be clearly defined, as the responsible genes have not been identified. After cloning a gene responsible for SM synthesis, SMS1, we established SM synthase-defective WR19L cells transfected with the human Fas gene (WR/Fas-SM(-)), and cells that have been functionally restored by transfection with SMS1 (WR/Fas-SMS1). We show that expression of membrane SM enhances Fas-mediated apoptosis through increasing DISC formation, activation of caspases, efficient translocation of Fas into lipid rafts, and subsequent Fas clustering. Furthermore, WR/Fas-SMS1 cells, but not WR/Fas-SM(-) cells, showed a considerable increase in ceramide generation within lipid rafts upon Fas stimulation. These data suggest that a membrane SM is important for Fas clustering through aggregation of lipid rafts, leading to Fas-mediated apoptosis.