The interaction between RIPK1 and FADD controls perinatal lethality and inflammation

• DOI: 10.1016/j.celrep.2024.114335
• Publication Date: 2024-06-12T23:46:20Z
• Authors: Diego A. Rodriguez; Bart Tummers; Jeremy J.P. Shaw; Giovanni Quarato; Ricardo Weinlich; James Cripps; Patrick Fitzgerald; Laura J. Janke; Stephane Pelletier; Jeremy Chase Craw...; Douglas R. Green
• Keywords: RIPK1; FADD; Caspase 8

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 long (cFLIPL) to regulate both extrinsic necroptosis. Here, we describe Ripk1-mutant animals (Ripk1R588E [RE]) in which interaction between FADD RIPK1 is disrupted, leading embryonic lethality. This lethality not prevented by further removal kinase activity Ripk1 K45A [REKA]). Both Ripk1RE Ripk1REKA survive adulthood upon ablation Ripk3. While mice effector mixed lineage kinase-like (MLKL), succumb inflammation after birth. In contrast, Mlkl does prevent embryos, but reach when MLKL caspase-8 are removed. Ablation nucleic acid sensor Zbp1 largely prevents embryos. Thus, RIPK1-FADD Z-DNA binding protein-1 (ZBP1)-induced, RIPK3-caspase-8-mediated lethality, affected RIPK1.