Published online 11 July 2005 doi:10.1084/jem.20041685
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 2, 249-259
Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis
Michihiko Miyaji1,2,
Zhe-Xiong Jin1,3,
Shohei Yamaoka4,
Ryuichi Amakawa2,
Shirou Fukuhara2,
Satoshi B. Sato5,6,
Toshihide Kobayashi5,
Naochika Domae7,
Tsuneyo Mimori1,
Eda T. Bloom8,
Toshiro Okazaki4, and
Hisanori Umehara1,3
1 Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
2 First Department of Internal Medicine, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan
3 Division of Hematology and Immunology, Department of Internal Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan
4 Department of Clinical Laboratory Medicine/Hematology, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
5 RIKEN, Wako, Saitama 351-0198, Japan
6 Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
7 Department of Medicine, Osaka Dental University, Hirakata, Osaka 573-1121, Japan
8 Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
CORRESPONDENCE Hisanori Umehara: umehara{at}kanazawa-med.ac.jp
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.
Abbreviations used: aSMase; acid sphingomyelinase, CTx; choleratoxin B; 
m, mitochondrial membrane potential; DISC, death-inducing signaling complex; FADD, Fas-associated death domain; FasL, Fas ligand; MBP, maltose-binding protein; PI, propidium iodide; SM; sphingomyelin.
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