1. Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction.
- Author
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Cruz AC, Ramaswamy M, Ouyang C, Klebanoff CA, Sengupta P, Yamamoto TN, Meylan F, Thomas SK, Richoz N, Eil R, Price S, Casellas R, Rao VK, Lippincott-Schwartz J, Restifo NP, and Siegel RM
- Subjects
- Animals, Apoptosis genetics, Autoimmunity genetics, Cell Differentiation genetics, Cell Differentiation immunology, Cells, Cultured, HEK293 Cells, Humans, Lipoylation immunology, Membrane Microdomains metabolism, Mice, Inbred C57BL, Mice, Knockout, Mutation, T-Lymphocytes immunology, T-Lymphocytes metabolism, fas Receptor genetics, fas Receptor metabolism, Apoptosis immunology, Autoimmunity immunology, Membrane Microdomains immunology, Mice, Transgenic, fas Receptor immunology
- 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.
- Published
- 2016
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