STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD
Konstantinos Kelepouras, Julia Saggau, Debora Bonasera, Christine Kiefer, Federica Locci, Hassan Rakhsh-Khorshid, Louisa Grauvogel, Ana Beatriz Varanda, Martin Peifer, Elena Loricchio, Antonella Montinaro, Marijana Croon, Aleksandra Trifunović, Giusi Prencipe, Antonella Insalaco, Fabrizio De Benedetti, Henning Walczak, Gianmaria Liccardi
Abstract
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 functional overlap between STING and ZBP1 as drivers of lethal dermatitis independently of tumour necrosis factor receptor 1 (TNFR1), identifying an aetiology of necroptotic inflammation. As gain-of-function mutations in human STING cause STING-associated vasculopathy with onset in infancy (SAVI), we assessed the role of STING-induced necroptosis in SAVI’s aetiology. Chronic activation of STING in patients orchestrates a necroptotic transcriptional program that is confirmed in the Sting1 N153S SAVI preclinical mouse model in which immune-cell-driven pathology and lethality are rescued by receptor-interacting serine/threonine-protein kinase 3 ( Ripk3 ) co-deletion. These findings establish STING-driven ZBP1-mediated necroptosis as a central pathogenic mechanism in both caspase-8-deficient inflammation and SAVI and suggest that targeting the ZBP1–RIPK3–MLKL axis holds therapeutic potential for interferonopathies characterized by excessive necroptosis.