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Lang, J.* ; Bergner, T.* ; Zinngrebe, J.* ; Lepelley, A.* ; Vill, K.* ; Leiz, S.* ; Wlaschek, M.* ; Wagner, M. ; Scharffetter-Kochanek, K.* ; Fischer-Posovszky, P.* ; Read, C.* ; Crow, Y.J.* ; Hirschenberger, M.* ; Sparrer, K.M.J.*

Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling.

EMBO Rep., DOI: 10.1038/s44319-025-00423-7 (2025)
DOI PMC
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Arf1 ; Interferon ; Interferonopathy ; Sting ; Cgas; Cyclic Gmp-amp; Structural Basis; Ikk-epsilon; Recruitment; 2nd-messenger; Trafficking; Activation; Retrieval; Inhibitor; Mechanism
ISSN (print) / ISBN 1469-221X
e-ISSN 1469-3178
Journal EMBO Reports
Publisher EMBO Press
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants Medical Faculty, Ulm University
German Federal Ministry of Education and Research (BMBF)
German Research Foundation (DFG)
DFG/Agence Nationale de la Recherche (ANR, France)
Inserm
ANR (ANR)
European Research Council
UK Medical Research Council Human Genetics Unit core grant
Agence Nationale de la Recherche (France) under the Investissements d'avenir programme
Margarete von Wrangell-Habilitationsprogramm (Ministry of Science, Research and Arts Baden-Wuerttemberg, European Social Fund)
DFG
Deutsche Forschungsgemeinschaft (DFG)