Letter | Published:

Functional complementation between FADD and RIP1 in embryos and lymphocytes

Nature volume 471, pages 373376 (17 March 2011) | Download Citation

  • A Corrigendum to this article was published on 14 March 2012

Abstract

FADD is a common adaptor shared by several death receptors for signalling apoptosis through recruitment and activation of caspase 8 (refs 1–3). Death receptors are essential for immune homeostasis, but dispensable during embryogenesis. Surprisingly, Fadd−/− mice die in utero4,5 and conditional deletion of FADD leads to impaired lymphocyte proliferation6,7. How FADD regulates embryogenesis and lymphocyte responses has been a long-standing enigma. FADD could directly bind to RIP1 (also known as RIPK1), a serine/threonine kinase that mediates both necrosis and NF-κB activation. Here we show that Fadd−/− embryos contain raised levels of RIP1 and exhibit massive necrosis. To investigate a potential in vivo functional interaction between RIP1 and FADD, null alleles of RIP1 were crossed into Fadd−/− mice. Notably, RIP1 deficiency allowed normal embryogenesis of Fadd−/− mice. Conversely, the developmental defect of Rip1−/− lymphocytes was partially corrected by FADD deletion. Furthermore, RIP1 deficiency fully restored normal proliferation in Fadd−/− T cells but not in Fadd−/− B cells. Fadd−/−Rip1−/− double-knockout T cells are resistant to death induced by Fas or TNF-α and show reduced NF-κB activity. Therefore, our data demonstrate an unexpected cell-type-specific interplay between FADD and RIP1, which is critical for the regulation of apoptosis and necrosis during embryogenesis and lymphocyte function.

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Acknowledgements

We thank M. Kelliher for providing Rip1+/− mice, S. Rosenberg, S. Waggoner, R. Welsh, V. Vanguri and Y. Liu for advice and technical assistance, X. Lin for discussions and suggestions, C. E. Calkins and K. Reinersmann for critical reading of the manuscript, and Z. Zhong for help with histology analysis. This study was supported in part by NIH grants CA95454, AI083915 and AI076788 awarded to J.Z. and AI083497 awarded to F.K.-M.C.; a W. W. Smith Charitable Trust grant, a TJU Enhancement grant, and a CONCERN Foundation grant awarded to J.Z. F.K.-M.C. is a member of the UMass DERC (DK32520) and is also supported in part by an NIH grant (AI017672).

Author information

Author notes

    • Xiaohui Zhou

    Present address: College of Life Science, Wenzhou Medical College, Zhejiang 325035, China.

Affiliations

  1. Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA

    • Haibing Zhang
    • , Xiaohui Zhou
    • , Jinghe Li
    •  & Jianke Zhang
  2. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

    • Thomas McQuade
    •  & Francis Ka-Ming Chan

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Contributions

J.Z. conceived and initiated the project. J.Z., F.K.-M.C. and H.Z. planned the experiments. All authors performed and analysed the experiments. J.Z. and F.K.-M.C. wrote the manuscript with contribution from H.Z.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Francis Ka-Ming Chan or Jianke Zhang.

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    Supplementary Information

    The file contains Supplementary Figures 1-8 with legends and Supplementary Table 1.

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https://doi.org/10.1038/nature09878

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