STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD

• 成果类型: Article
• 署名作者: 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
• 署名单位: University of Cologne; University of Cologne; University of Cologne; University of Cologne; University of Cologne; Max Planck Society; University of Cologne; IRCCS Bambino Gesu; University of London; University College London; University of Cologne; University of Cologne
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09536-4
• 发表日期: 2025-11-20
• 页码: 735-+
• 关键词: GENES-ASSOCIATED VASCULOPATHY; b-cell; caspase-8; ripk1; necrosis; roles; onset; activation; STIMULATOR; STABILITY

摘要

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.