Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis.

ABSTRACT: The absence of Caspase-8 or its adapter, Fas-associated death domain (FADD), results in activation of receptor interacting protein kinase-3 (RIPK3)- and mixed-lineage kinase-like (MLKL)-dependent necroptosis in vivo. Here, we show that spontaneous activation of RIPK3, phosphorylation of MLKL, and necroptosis in Caspase-8- or FADD-deficient cells was dependent on the nucleic acid sensor, Z-DNA binding protein-1 (ZBP1). We genetically engineered a mouse model by a single insertion of FLAG tag onto the N terminus of endogenous MLKL (Mlkl^FLAG/FLAG), creating an inactive form of MLKL that permits monitoring of phosphorylated MLKL without activating necroptotic cell death. Casp8^-/-Mlkl^FLAG/FLAG mice were viable and displayed phosphorylated MLKL in a

SUBMITTER: Rodriguez DA 

PROVIDER: S-EPMC9565532 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature