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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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).
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
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