RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development
- Anderton, H; Bandala-Sanchez, E; Simpson, DS; Rickard, JA; Ng, AP; Di Rago, L; Hall, C; Vince, JE; Silke, J; Liccardi, G; Feltham, R;
- Journal Title
- Cell Death and Differentiation
- Publication Type
- Journal Article in press
- RIPK1 is an essential downstream component of many pattern recognition and death receptors. RIPK1 can promote the activation of caspase-8 induced apoptosis and RIPK3-MLKL-mediated necroptosis, however, during development RIPK1 limits both forms of cell death. Accordingly, Ripk1(-/-) mice present with systemic cell death and consequent multi-organ inflammation, which is driven through the activation of both FADD-caspase-8 and RIPK3-MLKL signaling pathways causing perinatal lethality. TRADD is a death domain (DD) containing molecule that mediates signaling downstream of TNFR1 and the TLRs. Following the disassembly of the upstream receptor complexes either RIPK1 or TRADD can form a complex with FADD-caspase-8-cFLIP, via DD-DD interactions with FADD, facilitating the activation of caspase-8. We show that genetic deletion of Ripk1 licenses TRADD to complex with FADD-caspase-8 and activates caspase-8 during development. Deletion of Tradd provided no survival advantage to Ripk1(-/-) animals and yet was sufficient to reduce the systemic cell death and inflammation, rescue the intestinal and thymic histopathologies, reduce cleaved caspases in most tissues and rescue the anemia observed in Ripk1(-/-) neonates. Furthermore, deletion of Ripk3 is sufficient to rescue the neonatal lethality of Ripk1(-/-)Tradd(-/-) animals and delays but does not completely prevent early mortality. Although Ripk3 deletion provides a significant survival advantage, Ripk1(-/-)Tradd(-/-)Ripk3(-/-) animals die between 22 and 49 days, are runty compared to littermate controls and present with splenomegaly. These findings reveal a new mechanism by which RIPK1 limits apoptosis through blocking TRADD recruitment to FADD and preventing aberrant activation of caspase-8.
- WEHI Research Division(s)
- Cancer And Haematology; Inflammation; Cell Signalling And Cell Death; Population Health And Immunity
- PubMed ID
- Publisher's Version
- NHMRC Grants
- NHMRC/1081272, NHMRC/1046984, NHMRC/1057888, NHMRC/1101405, NHMRC/1060179, NHMRC/1052598,
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-09-14 02:33:43Last Modified: 2018-09-14 02:35:35