Functional complementation between FADD and RIP1 in embryos and lymphocytes - PubMed (original) (raw)
Functional complementation between FADD and RIP1 in embryos and lymphocytes
Haibing Zhang et al. Nature. 2011.
Erratum in
- Nature. 2012 Mar 22;483(7390):498
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 utero and conditional deletion of FADD leads to impaired lymphocyte proliferation. 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.
Figures
Figure 1. RIP1 deficiency rescues _FADD_−/− mice from embryonic necrosis and lethality
a, _FADD_−/− embryos exhibit massive necrosis and altered RIP1 and RIP3 expression. E12.5 wild type (WT, top panels) or _FADD_−/− embryos (bottom panels) were fixed in formalin. Left panels of hematoxylin and eosin (H&E) staining show extensive cell loss and pyknotic nuclei in the _FADD_−/− fetal liver. Middle and right panels indicate staining for RIP1or RIP3. b, E14.5 DKO embryos appear normal, contrasting the defective _FADD_−/− embryos.
Figure 2. FADD deficiency partially corrects the _RIP1_−/− T cell developmental defect by blocking apoptosis
Lymphocytes (a-b) in the chimeras of the indicated genotypes were analyzed. E18.5 fetal thymocytes of the indicated genotypes were treated with anti-Fas antibodies (c) or TNFα (d) and death responses determined 12 hours post stimulation. Error bars represent mean ± SEM of triplicates. T cells (e) and B cells (f) from NSG chimeras of the indicated genotypes were stimulated with anti-CD3 and anti-CD28 antibodies or with LPS, respectively. MEFs were stimulated with TNFα (g). NF-κB activation was indicated by the induction of p65 phosphorylation. β-actin, loading controls.
Figure 3. RIP1 deficiency rescues the _FADD_−/− T cell proliferation defect
a, T cells of the indicated wild type and chimera genotypes were stimulated with anti-CD3 and anti-CD28 antibodies. Proliferation was measured by [3H]-thymidine incorporation. b, Splenocytes of the indicated genotypes were transferred into _TCRαβ_−/− hosts and challenged with Pichinde virus (PV). Acute responses of the donor CD8 T cells to the indicated epitopes were determined. Anti-CD3 antibodies were used as control. c, B cells of the indicated genotypes were stimulated with LPS and proliferation was measured as in (a). Results shown (a and c) are mean ± SEM of triplicates.
Comment in
- Programmed cell death: Apoptosis meets necrosis.
Peter ME. Peter ME. Nature. 2011 Mar 17;471(7338):310-2. doi: 10.1038/471310a. Nature. 2011. PMID: 21412328 No abstract available. - Cell death: A killer puts a stop on necroptosis.
Wrighton KH. Wrighton KH. Nat Rev Mol Cell Biol. 2011 May;12(5):279. doi: 10.1038/nrm3101. Epub 2011 Mar 30. Nat Rev Mol Cell Biol. 2011. PMID: 21448226 No abstract available.
References
- Boldin MP, 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. 1995;270:7795–7798. - PubMed
- Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995;81:505–512. - PubMed
- Zhang J, Cado D, Chen A, Kabra NH, Winoto A. Absence of Fas-mediated apoptosis and T cell receptor-induced proliferation in FADD-deficient mice. Nature. 1998;392:296–300. - PubMed
- Yeh W-C, et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science. 1998;279:1954–1958. - PubMed
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