Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis

Abstract

Caspase-8 and Fas-associated death domain (FADD) play key roles in the regulation of cell death by necroptosis. The absence of either protein results in early embryonic lethality due to the activation of the kinase receptor interacting protein kinase-3 (RIPK3) and its phosphorylation of the necroptosis executioner, mixed-lineage kinase-like (MLKL). We genetically engineered and characterized a mouse model to monitor MLKL phosphorylation in the absence of necroptosis in vivo. Ablation of caspase-8 or FADD resulted in the transcriptional upregulation in several tissues of Z-DNA binding protein-1 (ZBP1), a cytosolic nucleic acid sensor capable of activating RIPK3, and ZBP1 was required for spontaneous phosphorylation of MLKL. Our findings provide a mechanism by which the FADD/Caspase-8 complex prevents necroptosis.