STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD.

ABSTRACT: Conditional deletion of caspase-8 in mouse epidermal keratinocytes (Casp8^E-KO) causes necroptosis-driven lethal dermatitis^1-7. Here we find that the loss of Casp8 leads to an accumulation of cytosolic DNA that is responsible for the activation of a cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-mediated transcriptional program. Genetic and biochemical evidence indicate that STING upregulates both Z-DNA-binding protein 1 (ZBP1) and mixed lineage kinase domain-like pseudokinase. Combined caspase-8-deficiency- and STING-activation-driven accumulation of Z-nucleic acids activates ZBP1 and triggers the formation of a ZBP1-RIPK1-RIPK3 complex independently of the FADD-RIPK1-RIPK3 complex, enabling execution of necroptosis. Genetically, we reveal a fun

SUBMITTER: Kelepouras K 

PROVIDER: S-EPMC12629989 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature