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Fas triggers an alternative, caspase-8–independent cell death pathway using the kinase RIP as effector molecule

Nature Immunology volume 1, pages 489–495 (2000)Cite this article

Abstract

Cell death is achieved by two fundamentally different mechanisms: apoptosis and necrosis. Apoptosis is dependent on caspase activation, whereas the caspase-independent necrotic signaling pathway remains largely uncharacterized. We show here that Fas kills activated primary T cells efficiently in the absence of active caspases, which results in necrotic morphological changes and late mitochondrial damage but no cytochrome c release. This Fas ligand–induced caspase-independent death is absent in T cells that are deficient in either Fas-associated death domain (FADD) or receptor-interacting protein (RIP). RIP is also required for necrotic death induced by tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL). In contrast to its role in nuclear factor κB activation, RIP requires its own kinase activity for death signaling. Thus, Fas, TRAIL and TNF receptors can initiate cell death by two alternative pathways, one relying on caspase-8 and the other dependent on the kinase RIP.

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Figure 1: FasL-induced and activation-induced cell death in primary human and murine T cells is insensitive to the caspase inhibitor zVAD-fmk.
Figure 2: FasL-mediated, caspase-independent cell death in T cells requires FADD.
Figure 3: RIP binds to Fas and signals necrotic T cell death.
Figure 4: FasL-induced, caspase-independent T cell death is associated with necrotic morphological changes that are independent of cytochrome c release.
Figure 5: TNF and TRAIL signal caspase-independent cell death in T cells.
Figure 6: Putative model of death receptor-induced necrosis.

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Acknowledgements

We are grateful to A. Strasser for the gift of the CEM-FADD/DN and CEM-CrmA clones and J. Blenis for the FADD and caspase-8 deficient Jurkat cells. We thank K. Burns and L. French for helpful comments and C. Mattmann for technical assistance.

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Authors and Affiliations

  1. Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, Epalinges, CH-1066, Switzerland

    Nils Holler, Rossana Zaru, Olivier Micheau, Margot Thome, Antoine Attinger, Salvatore Valitutti, Jean-Luc Bodmer, Pascal Schneider & Jürg Tschopp

  2. Department of Molecular Biology, Massachussets General Hospital, Boston, 02114, MA, USA

    Brian Seed

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Correspondence to Jürg Tschopp.

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Holler, N., Zaru, R., Micheau, O. et al. Fas triggers an alternative, caspase-8–independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1, 489–495 (2000). https://doi.org/10.1038/82732

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