Rodriguez, Diego A.Tummers, BartShaw, Jeremy J. P.Quarato, GiovanniWeinlich, RicardoCripps, JamesFitzgerald, PatrickJanke, Laura J.Pelletier, StephaneCrawford, Jeremy ChaseGreen, Douglas R.2024-09-232024-09-232024Rodriguez DA, Tummers B, Shaw JJP, et al. The interaction between RIPK1 and FADD controls perinatal lethality and inflammation. Cell Rep. 2024;43(6):114335. doi:10.1016/j.celrep.2024.114335https://hdl.handle.net/1805/43487Perturbation 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.en-USPublisher PolicyImmunologyCaspase-8ApoptosisNecroptosisArticle