Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling
Tight control of cGAS-STING-mediated DNA sensing is crucial to avoid auto-inflammation. The GTPase ADP-ribosylation factor 1 (ARF1) is crucial to maintain cGAS-STING homeostasis and various pathogenic ARF1 variants are associated with type I interferonopathies. Functional ARF1 inhibits STING activity by maintaining mitochondrial integrity and facilitating COPI-mediated retrograde STING trafficking and deactivation. Yet the factors governing the two distinct functions of ARF1 remained unexplored. Here, we dissect ARF1's dual role by a comparative analysis of disease-associated ARF1 variants and their impact on STING signalling. We identify a de novo heterozygous s.55 C > T/p.R19C ARF1 variant in a patient with type I interferonopathy symptoms. The GTPase-deficient variant ARF1 R19C selectively disrupts COPI binding and retrograde transport of STING, thereby prolonging innate immune activation without affecting mitochondrial integrity. Treatment of patient fibroblasts in vitro with the STING signalling inhibitors H-151 and amlexanox reduces chronic interferon signalling. Summarizing, our data reveal the molecular basis of a ARF1-associated type I interferonopathy allowing dissection of the two roles of ARF1, and suggest that pharmacological targeting of STING may alleviate ARF1-associated auto-inflammation.
Authors
- Alice Lepelley (ORCID: https://orcid.org/0000-0001-8656-7291)
- Meinhard Wlaschek
- Steffen Leiz (ORCID: https://orcid.org/0000-0002-3279-8745)
- Yanick Joseph Crow (ORCID: https://orcid.org/0000-0001-7211-7564)
- Karin Scharffetter‐Kochanek (ORCID: https://orcid.org/0000-0002-9655-685X)
- Julia Zinngrebe
- Konstantin M. J. Sparrer (ORCID: https://orcid.org/0000-0002-8682-1779)
- Tim Bergner (ORCID: https://orcid.org/0000-0002-6411-1071)
- Matias Wagner (ORCID: https://orcid.org/0000-0002-4454-8823)
- Pamela Fischer‐Posovszky (ORCID: https://orcid.org/0000-0003-3402-9840)
- Katharina Vill (ORCID: https://orcid.org/0000-0003-1925-7538)
- Maximilian Hirschenberger (ORCID: https://orcid.org/0000-0001-8766-1271)
- Johannes Lang (ORCID: https://orcid.org/0000-0002-7387-795X)
- Clarissa Read (ORCID: https://orcid.org/0000-0002-4632-2684)
Institutions
- Inserm (FR)
- Universität Ulm (DE)
- Université Paris Cité (FR)
- German Center for Neurodegenerative Diseases (DE)
- TUM Klinikum (DE)
- Helmholtz Zentrum München (DE)
- German Center for Pediatric and Adolescent Rheumatology (DE)
- München Klinik (DE)
- German Centre for Cardiovascular Research (DE)
- Institute of Genetics and Cancer (GB)
- Institut des Maladies Génétiques Imagine (FR)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Edinburgh (GB)
Publication Details
- Journal
- EMBO Reports
- Published
- 2025-03-24
- DOI
- https://doi.org/10.1038/s44319-025-00423-7
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Bundesministerium für Bildung und Forschung
- Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
- Medical Research Council
- European Research Council