Letter | Published:

Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis

Nature volume 471, pages 363367 (17 March 2011) | Download Citation

Abstract

Caspase-8 has two opposing biological functions—it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development1, T-lymphocyte activation2, and resistance to necrosis induced by tumour necrosis factor-α (TNF-α) and related family ligands3,4. Here we show that development of caspase-8-deficient mice is completely rescued by ablation of receptor interacting protein kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand (also known as FAS and FASLG, respectively), and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIPL, also known as CFLAR), and this complex is required for the protective function.

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Acknowledgements

The authors thank W. J. Kaiser and E. S. Mocarski for their discussions and material support. We thank Ariad Pharmaceutical for providing the homo- and heterodimerization reagents. We thank the members of the St. Jude Immunology FACS core facility, as well as M. Johnson, L. Janke and the St. Jude Veterinary Pathology Core. We also thank the St. Jude Hartwell Center. This work was supported by NIH grant AI44828 to D.R.G. and CA69381 to G.S.S., as well as CIHR grant MOP 36537 to R.H. C.P.D. was supported by a fellowship grant from the Sass Foundation for Medical Research. This work was also supported by ALSAC.

Author information

Affiliations

  1. Dept. of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Andrew Oberst
    • , Christopher P. Dillon
    • , Ricardo Weinlich
    • , Laura L. McCormick
    • , Patrick Fitzgerald
    •  & Douglas R. Green
  2. Program in Apoptosis and Cell Death Research, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA

    • Cristina Pop
    •  & Guy S. Salvesen
  3. Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada

    • Razq Hakem

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Contributions

A.O. and D.R.G conceived the study and designed the experiments. C.P.D. and L.L.M. designed and conducted mouse breedings. C.P.D., R.W. and A.O. carried out all experiments involving mice and tissues from mice. A.O. and R.W. carried out experiments involving cell lines and produced western blots. P.F. provided essential logistical and administrative support. C.P. and G.S.S. conceived, designed and carried out in vitro dimerization assays and CrmA inhibition studies. R.H. produced the caspase-8flox animals that made the study possible.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Douglas R. Green.

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DOI

https://doi.org/10.1038/nature09852

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