Membrane-bound Fas ligand only is essential for Fas-induced apoptosis
Open accessAbstract
Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice and humans. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding. Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL (FasL(Deltas/Deltas)) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasL(Deltam/Deltam)) could not kill cells through Fas activation. FasL(Deltam/Deltam) mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL(gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL(Deltam/Deltam) mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL(gld/gld) mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.
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Ability of some death receptors including TNFR1 to promote NF-κB activation over CASP8 activation depends on degree of receptor oligomerization, scaffolding functions of CASP8, and assembly of TNFR1-like complexes containing RIPK1 and LUBAC.
“The ability of some death receptors including TNFR1 to promote NF-κB activation over CASP8 activation appears to depend on the degree of receptor oligomerization (i.e., trimerization vs. higher-order multimerization) [343], the scaffolding (i.e., non-enzymatic) functions of CASP8, and the consequent assembly of TNFR1-like complexes containing RIPK1 and LUBAC [272, 286, 344].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [343]
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- Authors
- O’ Reilly, L. A., Tai, L., Lee, L., Kruse, E. A., Grabow, S., Fairlie, W. D., Haynes, N. M., Tarlinton, D. M., Zhang, J.-G., Belz, G. T., Smyth, M. J., Bouillet, P., Robb, L., & Strasser, A.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- Corresponding author
- Strasser, Andreas
- ORCID
- Venue
- Nature
- Published
- 2009-10
- Volume
- 461
- Issue
- 7264
- Pages
- 659-663
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2785124
- OpenAlex
- W1969187681
- Cited by
- 400
- References
- 42
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 18 · 2023: 15 · 2022: 17 · 2021: 24 · 2020: 16 · 2019: 28 · 2018: 25 · 2017: 29 · 2016: 23 · 2015: 23 · 2014: 31 · 2013: 35 · 2012: 30
- FWCI
- 12.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- National Cancer Institute (CA-80188-6, R01CA043540, R01CA080188)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- Fas ligand, soluble Fas ligand, Fas, apoptosis, autoimmunity, systemic lupus erythematosus, lymphadenopathy, hypergammaglobulinemia, carcinogenesis, gene-targeted mice
- MeSH terms
- AICDA (Activation-Induced Cytidine Deaminase), Animals, Antibodies, Antinuclear, Cell Membrane, Cytidine Deaminase, Cytotoxicity, Immunologic, Glomerulonephritis, Hypergammaglobulinemia, Lupus Erythematosus, Systemic, Lymphatic Diseases, Mice, Inbred C57BL, Mutation, Splenomegaly, T-Lymphocytes, Apoptosis, fas Receptor, Mice, Fas Ligand Protein, Histiocytic Sarcoma
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