title: Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction.
abstract: Mutations affecting the apoptosis-inducing function of the Fas/CD95 TNF-family receptor result in autoimmune and lymphoproliferative disease. However, Fas can also costimulate T-cell activation and promote tumour cell growth and metastasis. Palmitoylation at a membrane proximal cysteine residue enables Fas to localize to lipid raft microdomains and induce apoptosis in cell lines. Here, we show that a palmitoylation-defective Fas C194V mutant is defective in inducing apoptosis in primary mouse T cells, B cells and dendritic cells, while retaining the ability to enhance naive T-cell differentiation. Despite inability to efficiently induce cell death, the Fas C194V receptor prevents the lymphoaccumulation and autoimmunity that develops in Fas-deficient mice. These findings indicate that induction of apoptosis through Fas is dependent on receptor palmitoylation in primary immune cells, and Fas may prevent autoimmunity by mechanisms other than inducing apoptosis.
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Cruz
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Madhu
authors.initials: M
authors.lastname: Ramaswamy
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ouyang
authors.affiliation: Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Center For Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.affiliation: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, Maryland 20892, USA.
authors.forename: Prabuddha
authors.initials: P
authors.lastname: Sengupta
authors.affiliation: Center For Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USA.|Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Tori N
authors.initials: TN
authors.lastname: Yamamoto
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Françoise
authors.initials: F
authors.lastname: Meylan
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Stacy K
authors.initials: SK
authors.lastname: Thomas
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Richoz
authors.affiliation: Center For Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Eil
authors.affiliation: Clinical Genomics Unit, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland 20892, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Price
authors.affiliation: Genomics and Immunity Branch, NIAMS, Bethesda, Maryland 20892, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.affiliation: Clinical Genomics Unit, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland 20892, USA.
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.affiliation: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, Maryland 20892, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lippincott-Schwartz
authors.affiliation: Center For Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USA.|Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Richard M
authors.identifier: 0000-0001-5953-9893
authors.initials: RM
authors.lastname: Siegel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D054878:Lipoylation / Q000276:immunology; D021962:Membrane Microdomains / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D019014:fas Receptor