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Functional complementation between FADD and RIP1 in embryos and lymphocytes

A Corrigendum to this article was published on 14 March 2012


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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Figure 1: RIP1 deficiency rescues Fadd −/− mice from embryonic necrosis and lethality.
Figure 2: FADD deficiency partially corrects the Rip1 −/− T-cell developmental defect by blocking apoptosis.
Figure 3: RIP1 deficiency rescues the Fadd −/− T-cell proliferation defect.


  1. Boldin, M. P. et al. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J. Biol. Chem. 270, 7795–7798 (1995)

    Article  CAS  Google Scholar 

  2. Chinnaiyan, A. M., O’Rourke, K., Tewari, M. & Dixit, V. M. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81, 505–512 (1995)

    Article  CAS  Google Scholar 

  3. Zhang, J. & Winoto, A. A mouse Fas-associated protein with homology to the human Mort1/FADD protein is essential for Fas-induced apoptosis. Mol. Cell. Biol. 16, 2756–2763 (1996)

    Article  CAS  Google Scholar 

  4. Zhang, J., Cado, D., Chen, A., Kabra, N. H. & Winoto, A. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392, 296–300 (1998)

    Article  CAS  ADS  Google Scholar 

  5. Yeh, W.-C. et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279, 1954–1958 (1998)

    Article  CAS  ADS  Google Scholar 

  6. Zhang, Y. et al. Conditional Fas-associated death domain protein (FADD):GFP knockout mice reveal FADD is dispensable in thymic development but essential in peripheral T cell homeostasis. J. Immunol. 175, 3033–3044 (2005)

    Article  CAS  Google Scholar 

  7. Imtiyaz, H. Z. et al. The Fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells. J. Immunol. 176, 6852–6861 (2006)

    Article  CAS  Google Scholar 

  8. Nagata, S. Apoptosis by death factor. Cell 88, 355–365 (1997)

    Article  CAS  Google Scholar 

  9. Boldin, M. P., Goncharov, T. M., Goltsev, Y. V. & Wallach, D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNF receptor-induced cell death. Cell 85, 803–815 (1996)

    Article  CAS  Google Scholar 

  10. Muzio, M. et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85, 817–827 (1996)

    Article  CAS  Google Scholar 

  11. Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature Immunol. 1, 489–495 (2000)

    Article  CAS  ADS  Google Scholar 

  12. Chan, F. K.-M. et al. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J. Biol. Chem. 278, 51613–51621 (2003)

    Article  CAS  Google Scholar 

  13. Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1–RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009)

    Article  CAS  Google Scholar 

  14. He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009)

    Article  CAS  Google Scholar 

  15. Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009)

    Article  CAS  ADS  Google Scholar 

  16. Kelliher, M. A. et al. The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8, 297–303 (1998)

    Article  CAS  Google Scholar 

  17. Cusson, N., Oikemus, S., Kilpatrick, E. D., Cunningham, L. & Kelliher, M. The death domain kinase RIP protects thymocytes from tumor necrosis factor receptor type 2-induced cell death. J. Exp. Med. 196, 15–26 (2002)

    Article  CAS  Google Scholar 

  18. Shen, H. M. et al. Essential roles of receptor-interacting protein and TRAF2 in oxidative stress-induced cell death. Mol. Cell. Biol. 24, 5914–5922 (2004)

    Article  CAS  Google Scholar 

  19. Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chem. Biol. 1, 112–119 (2005)

    Article  CAS  Google Scholar 

  20. Rosenberg, S., Zhang, H. & Zhang, J. FADD deficiency impairs early hematopoiesis in the bone marrow. J. Immunol. 186, 203–213 (2011)

    Article  CAS  Google Scholar 

  21. Varfolomeev, E. E. et al. Targeted disruption of the mouse caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9, 267–276 (1998)

    Article  CAS  Google Scholar 

  22. Ch’en, I. L. et al. Antigen-mediated T cell expansion regulated by parallel pathways of death. Proc. Natl Acad. Sci. USA 105, 17463–17468 (2008)

    Article  ADS  Google Scholar 

  23. Osborn, S. L. et al. Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis. Proc. Natl Acad. Sci. USA 107, 13034–13039 (2010)

    Article  CAS  ADS  Google Scholar 

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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).

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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.

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Correspondence to Francis Ka-Ming Chan or Jianke Zhang.

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The authors declare no competing financial interests.

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Zhang, H., Zhou, X., McQuade, T. et al. Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 471, 373–376 (2011).

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