Kelepouras, Konstantinos; Saggau, Julia; Bonasera, Debora; Kiefer, Christine; Locci, Federica; Rakhsh-Khorshid, Hassan; Grauvogel, Louisa; ... Liccardi, Gianmaria; + view all Kelepouras, Konstantinos; Saggau, Julia; Bonasera, Debora; Kiefer, Christine; Locci, Federica; Rakhsh-Khorshid, Hassan; Grauvogel, Louisa; Varanda, Ana Beatriz; Peifer, Martin; Loricchio, Elena; Montinaro, Antonella; Croon, Marijana; Trifunovic, Aleksandra; Prencipe, Giusi; Insalaco, Antonella; De Benedetti, Fabrizio; Walczak, Henning; Liccardi, Gianmaria; - view fewer (2025) STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD. Nature 10.1038/s41586-025-09536-4. (In press).

Text s41586-025-09536-4_reference.pdf - Accepted Version Access restricted to UCL open access staff until 21 February 2026. Download (197MB)

Abstract

Conditional deletion of Caspase-8 in epidermal keratinocytes (Casp8E-KO) causes necroptosis-driven lethal dermatitis1-7. Here, we discover that Casp8 loss leads to accumulation of cytosolic DNA responsible for the activation of a cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon (IFN) gene (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 (MLKL). Combined Casp8-deficiency- and STING-activation-driven accumulation of Z-nuclei acids, activates ZBP1 and triggers formation of a ZBP1-RIPK1-RIPK3 complex independently of FADD-RIPK1-RIPK3 complex enabling necroptosis execution. Genetically, we reveal a functional overlap between STING and ZBP1 as drivers of lethal dermatitis independently of TNFR1, uncovering a novel aetiology of necroptotic inflammation. Since 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 which is confirmed in the N153S-SAVI preclinical mouse model where immune cell-driven pathology and lethality are remarkably rescued by RIPK3 co-deletion. These findings establish STING-driven ZBP1-mediated necroptosis as a central pathogenic mechanism in both Casp8-deficient inflammation and SAVI and suggest that targeting the ZBP1-RIPK3-MLKL axis holds therapeutic potential for interferonopathies characterised by excessive necroptosis.

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