The interaction between RIPK1 and FADD controls perinatal lethality and inflammation
Diego A. Rodriguez,
Bart Tummers,
Jeremy J.P. Shaw,
Giovanni Quarato,
Ricardo Weinlich,
James Cripps,
Patrick Fitzgerald,
Laura J. Janke,
Stephane Pelletier,
Jeremy Chase Crawford,
Douglas R. Green
Affiliations
Diego A. Rodriguez
Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Bart Tummers
Centre for Inflammation Biology & Cancer Immunology (CIBCI), Department of Inflammation Biology, School of Immunology & Microbial Sciences, King’s College London, London SE1 1UL, UK; Corresponding author
Jeremy J.P. Shaw
Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Giovanni Quarato
Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Treeline Biosciences, San Diego, CA 92121, USA
Ricardo Weinlich
Hospital Israelita Albert Einstein, São Paulo, Brazil
James Cripps
Center for Cancer Immunology and Immunotherapy, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA
Patrick Fitzgerald
Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Laura J. Janke
Department of Pathology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Stephane Pelletier
Department of Medical and Molecular Genetics, Indiana University Genome Editing Center, Indiana University School of Medicine, Indiana University, Indianapolis, IA 46902, USA
Jeremy Chase Crawford
Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Douglas R. Green
Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Corresponding author
Summary: Perturbation of the apoptosis and necroptosis pathways critically influences embryogenesis. Receptor-associated protein kinase-1 (RIPK1) interacts with Fas-associated via death domain (FADD)-caspase-8-cellular Flice-like inhibitory protein long (cFLIPL) to regulate both extrinsic apoptosis and necroptosis. Here, we describe Ripk1-mutant animals (Ripk1R588E [RE]) in which the interaction between FADD and RIPK1 is disrupted, leading to embryonic lethality. This lethality is not prevented by further removal of the kinase activity of Ripk1 (Ripk1R588E K45A [REKA]). Both Ripk1RE and Ripk1REKA animals survive to adulthood upon ablation of Ripk3. While embryonic lethality of Ripk1RE mice is prevented by ablation of the necroptosis effector mixed lineage kinase-like (MLKL), animals succumb to inflammation after birth. In contrast, Mlkl ablation does not prevent the death of Ripk1REKA embryos, but animals reach adulthood when both MLKL and caspase-8 are removed. Ablation of the nucleic acid sensor Zbp1 largely prevents lethality in both Ripk1RE and Ripk1REKA embryos. Thus, the RIPK1-FADD interaction prevents Z-DNA binding protein-1 (ZBP1)-induced, RIPK3-caspase-8-mediated embryonic lethality, affected by the kinase activity of RIPK1.
