Functional complementation between FADD and RIP1 in embryos and lymphocytes (original) (raw)
- Letter
- Published: 02 March 2011
- Xiaohui Zhou1 nAff3,
- Thomas McQuade2,
- Jinghe Li1,
- Francis Ka-Ming Chan2 &
- …
- Jianke Zhang1
Nature volume 471, pages 373–376 (2011)Cite this article
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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).
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- Xiaohui Zhou
Present address: Present address: College of Life Science, Wenzhou Medical College, Zhejiang 325035, China.,
Authors and Affiliations
- Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, USA
Haibing Zhang, Xiaohui Zhou, Jinghe Li & Jianke Zhang - Department of Pathology, University of Massachusetts Medical School, Worcester, 01655, Massachusetts, USA
Thomas McQuade & Francis Ka-Ming Chan
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- Haibing Zhang
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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.
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Correspondence toFrancis 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). https://doi.org/10.1038/nature09878
- Received: 02 December 2010
- Accepted: 27 January 2011
- Published: 02 March 2011
- Issue Date: 17 March 2011
- DOI: https://doi.org/10.1038/nature09878
Editorial Summary
Shared function of FADD and RIPK1
Regulation of cell death is vital for embryonic development and homeostasis in somatic cells, and the Fas-associated death domain (FADD) is a critical signalling adaptor for extrinsic apoptotic pathways. In a study of potential interactions between FADD and receptor interacting protein kinase-1 (RIP1/RIPK1), double deficiency of FADD and RIPK1 is shown to rescue the defects in embryonic development and lymphocyte proliferation seen in mice with single gene deficiencies. This suggests that FADD (presumably in conjunction with caspase-8 and c-FLIP) keeps necrosis in check by causing cleavage of RIPK1.