Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction

Anthony C. Cruz, Madhu Ramaswamy, Claudia Ouyang, Christopher A. Klebanoff, Prabuddha Sengupta, Tori N. Yamamoto, Françoise Meylan, Stacy K. Thomas, Nathan Richoz, Robert Eil, Susan Price, Rafael Casellas, V. Koneti Rao, Jennifer Lippincott-Schwartz, Nicholas P. Restifo and Richard M. Siegel ()
Additional contact information
Anthony C. Cruz: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH)
Madhu Ramaswamy: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH)
Claudia Ouyang: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH)
Christopher A. Klebanoff: Memorial Sloan Kettering Cancer Center
Prabuddha Sengupta: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH
Tori N. Yamamoto: Center For Cancer Research, National Cancer Institute (NCI), NIH
Françoise Meylan: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH)
Stacy K. Thomas: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH)
Nathan Richoz: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH)
Robert Eil: Center For Cancer Research, National Cancer Institute (NCI), NIH
Susan Price: Clinical Genomics Unit, National Institute of Allergy and Infectious Diseases (NIAID), NIH
Rafael Casellas: Genomics and Immunity Branch, NIAMS
V. Koneti Rao: Clinical Genomics Unit, National Institute of Allergy and Infectious Diseases (NIAID), NIH
Jennifer Lippincott-Schwartz: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH
Nicholas P. Restifo: Center For Cancer Research, National Cancer Institute (NCI), NIH
Richard M. Siegel: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH)

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13895

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