Journal article
RIPK1-and RIPK3-induced cell death mode is determined by target availability
WD Cook, DM Moujalled, TJ Ralph, P Lock, SN Young, JM Murphy, DL Vaux
Cell Death and Differentiation | Published : 2014
DOI: 10.1038/cdd.2014.70
Abstract
Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following death receptor ligation. To study the requirements for RIPK-triggered cell death in the absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3 that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell death by caspase-or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death by an MLKL-dependent mechanism but, surprisingly, also induced death mediated by FADD, caspase 8 and RIPK1. Catalytically active RIPK3 kinase domains were essential..
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Awarded by Australian Research Council
Funding Acknowledgements
This work was funded by NHMRC Grants 1016701 (to DLV) and 1057905 (to JMM) and Fellowship 1020136 (to DLV), and Cancer Council Victoria Grant 1044722 (to DLV and WDC), Cure Cancer Australia Foundation Grant 1050301 (to DMM), a Center Grant from Leukemia and Lymphoma Society (US) 7413-07, an ARC Future Fellowship FT100100100 (to JMM), and was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS (361646). We thank Toru Okamoto for the doxycycline-inducible vector, Francis Chan for the Fadd<SUP>-/-</SUP> MEFs, Kim Newton and Vishva Dixit for Ripk3<SUP>-/-</SUP> mice and Stephen Hedrick for caspase 8 conditional knockout mice.