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; Richard M. Siegel

doi:10.1038/ncomms13895

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, Richard M. Siegel

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

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.

Original language	English (US)
Article number	13895
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13895
State	Published - Dec 23 2016
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Cruz, A. C., Ramaswamy, M., Ouyang, C., Klebanoff, C. A., Sengupta, P., Yamamoto, T. N., Meylan, F., Thomas, S. K., Richoz, N., Eil, R., Price, S., Casellas, R., Rao, V. K., Lippincott-Schwartz, J., Restifo, N. P., & Siegel, R. M. (2016). Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction. Nature communications, 7, Article 13895. https://doi.org/10.1038/ncomms13895

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 & Siegel, RM 2016, 'Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction', Nature communications, vol. 7, 13895. https://doi.org/10.1038/ncomms13895

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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.",

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AU - Sengupta, Prabuddha

AU - Yamamoto, Tori N.

AU - Meylan, Françoise

AU - Thomas, Stacy K.

AU - Richoz, Nathan

AU - Eil, Robert

AU - Price, Susan

AU - Casellas, Rafael

AU - Rao, V. Koneti

AU - Lippincott-Schwartz, Jennifer

AU - Restifo, Nicholas P.

AU - Siegel, Richard M.

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AB - 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.

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

Abstract

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