Journal Article

DZNE-2025-00606

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling.

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.Extern* ; Sparrer, K. M. J. (Last author)DZNE*

2025
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s44319-025-00423-7

Abstract: 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.

Keyword(s): Humans (MeSH) ; Nucleotidyltransferases: metabolism (MeSH) ; Nucleotidyltransferases: genetics (MeSH) ; ADP-Ribosylation Factor 1: genetics (MeSH) ; ADP-Ribosylation Factor 1: metabolism (MeSH) ; Signal Transduction (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Membrane Proteins: genetics (MeSH) ; Mutation (MeSH) ; Fibroblasts: metabolism (MeSH) ; Interferon Type I: metabolism (MeSH) ; Mitochondria: metabolism (MeSH) ; HEK293 Cells (MeSH) ; ARF1 ; Interferon ; Interferonopathy ; STING ; cGAS ; STING1 protein, human ; Nucleotidyltransferases ; ADP-Ribosylation Factor 1 ; Membrane Proteins ; cGAS protein, human ; ARF1 protein, human ; Interferon Type I

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Contributing Institute(s):

1. Neurovirology and Neuroinflammation (AG Sparrer)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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