Universität zu Köln

Kelepouras, Konstantinos ORCID: 0000-0003-4257-9404, Saggau, Julia ORCID: 0000-0002-9908-5467, Bonasera, Debora ORCID: 0000-0003-1567-2283, Kiefer, Christine ORCID: 0009-0005-1577-8565, Locci, Federica ORCID: 0000-0001-5443-0717, Rakhsh-Khorshid, Hassan ORCID: 0000-0002-5801-2368, Grauvogel, Louisa ORCID: 0009-0001-9460-0810, Varanda, Ana Beatriz, Peifer, Martin ORCID: 0000-0002-5243-5503, Loricchio, Elena, Montinaro, Antonella, Croon, Marijana ORCID: 0000-0001-5797-5413, Trifunovic, Aleksandra ORCID: 0000-0002-5472-3517, Prencipe, Giusi, Insalaco, Antonella, De Benedetti, Fabrizio, Walczak, Henning ORCID: 0000-0002-6312-4591 and Liccardi, Gianmaria ORCID: 0000-0002-2662-1281 (2025). STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD. Nature, 647. pp. 735-746. Nature Publ. Group. ISSN 1476-4687

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Abstract

Conditional deletion of caspase-8 in mouse epidermal keratinocytes (Casp8E-KO) causes necroptosis-driven lethal dermatitis1–7. 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 Sting1N153S 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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Kelepouras, Konstantinos UNSPECIFIED https://orcid.org/0000-0003-4257-9404 UNSPECIFIED Saggau, Julia UNSPECIFIED https://orcid.org/0000-0002-9908-5467 UNSPECIFIED Bonasera, Debora UNSPECIFIED https://orcid.org/0000-0003-1567-2283 UNSPECIFIED Kiefer, Christine UNSPECIFIED https://orcid.org/0009-0005-1577-8565 UNSPECIFIED Locci, Federica UNSPECIFIED https://orcid.org/0000-0001-5443-0717 UNSPECIFIED Rakhsh-Khorshid, Hassan UNSPECIFIED https://orcid.org/0000-0002-5801-2368 UNSPECIFIED Grauvogel, Louisa UNSPECIFIED https://orcid.org/0009-0001-9460-0810 UNSPECIFIED Varanda, Ana Beatriz UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Martin UNSPECIFIED https://orcid.org/0000-0002-5243-5503 UNSPECIFIED Loricchio, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Montinaro, Antonella UNSPECIFIED UNSPECIFIED UNSPECIFIED Croon, Marijana UNSPECIFIED https://orcid.org/0000-0001-5797-5413 UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED https://orcid.org/0000-0002-5472-3517 UNSPECIFIED Prencipe, Giusi UNSPECIFIED UNSPECIFIED UNSPECIFIED Insalaco, Antonella UNSPECIFIED UNSPECIFIED UNSPECIFIED De Benedetti, Fabrizio UNSPECIFIED UNSPECIFIED UNSPECIFIED Walczak, Henning UNSPECIFIED https://orcid.org/0000-0002-6312-4591 UNSPECIFIED Liccardi, Gianmaria UNSPECIFIED https://orcid.org/0000-0002-2662-1281 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-790664
Identification Number:	10.1038/s41586-025-09536-4
Journal or Publication Title:	Nature
Volume:	647
Page Range:	pp. 735-746
Date:	20 November 2025
Publisher:	Nature Publ. Group
ISSN:	1476-4687
Language:	English
Faculty:	Central Institutions / Interdisciplinary Research Centers External institution Faculty of Medicine
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Plant Breeding Research CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Medicine > Biochemie > Institut I für Biochemie Faculty of Medicine > Weitere > Centrum für integrierte Onkologie (CIO) Zentrum für Molekulare Medizin
Subjects:	Chemistry and allied sciences Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79066