Details

Autor(en) / Beteiligte

• Rodriguez, Diego A.
• Tummers, Bart
• Shaw, Jeremy J.P.
• Quarato, Giovanni
• Weinlich, Ricardo
• Cripps, James
• Fitzgerald, Patrick
• Janke, Laura J.
• Pelletier, Stephane
• Crawford, Jeremy Chase
• Green, Douglas R.

Titel

The interaction between RIPK1 and FADD controls perinatal lethality and inflammation

Ist Teil von

• Cell reports (Cambridge), 2024-06, Vol.43 (6), p.114335-114335, Article 114335

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •A mutation in RIPK1 (R588E) disrupts the interaction between RIPK1 and FADD•Disrupting the interaction between RIPK1 and FADD leads to embryonic lethality•The kinase activity of RIPK1 R588E prevents RIPK3-mediated embryonic lethality•Zbp1 ablation partially prevents RIPK1 R588E-mediated embryonic lethality Rodriguez et al. show that breaking the interaction between the cell-death-regulating proteins RIPK1 and FADD results in developmental death and inflammation that are initiated by the cellular receptor ZBP1 and regulated by the kinase activity of RIPK1, shedding light on the intricate functions of this interaction.