Home > Publications Database > Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling. > print

001     278573
005     20250613100543.0
024 7 _ |a 10.1038/s44319-025-00423-7
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024 7 _ |a 1469-221X
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037 _ _ |a DZNE-2025-00606
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Lang, Johannes
|b 0
245 _ _ |a Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling.
260 _ _ |a [London]
|c 2025
|b Nature Publishing Group UK
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520 _ _ |a 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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650 _ 7 |a ARF1
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650 _ 7 |a Interferon
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650 _ 7 |a Interferonopathy
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650 _ 7 |a STING
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650 _ 7 |a cGAS
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650 _ 7 |a STING1 protein, human
|2 NLM Chemicals
650 _ 7 |a Nucleotidyltransferases
|0 EC 2.7.7.-
|2 NLM Chemicals
650 _ 7 |a ADP-Ribosylation Factor 1
|0 EC 3.6.5.2
|2 NLM Chemicals
650 _ 7 |a Membrane Proteins
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650 _ 7 |a cGAS protein, human
|0 EC 2.7.7.-
|2 NLM Chemicals
650 _ 7 |a ARF1 protein, human
|0 EC 3.6.5.2
|2 NLM Chemicals
650 _ 7 |a Interferon Type I
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Nucleotidyltransferases: metabolism
|2 MeSH
650 _ 2 |a Nucleotidyltransferases: genetics
|2 MeSH
650 _ 2 |a ADP-Ribosylation Factor 1: genetics
|2 MeSH
650 _ 2 |a ADP-Ribosylation Factor 1: metabolism
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
650 _ 2 |a Membrane Proteins: metabolism
|2 MeSH
650 _ 2 |a Membrane Proteins: genetics
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Fibroblasts: metabolism
|2 MeSH
650 _ 2 |a Interferon Type I: metabolism
|2 MeSH
650 _ 2 |a Mitochondria: metabolism
|2 MeSH
650 _ 2 |a HEK293 Cells
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700 1 _ |a Bergner, Tim
|b 1
700 1 _ |a Zinngrebe, Julia
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700 1 _ |a Lepelley, Alice
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700 1 _ |a Vill, Katharina
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700 1 _ |a Leiz, Steffen
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700 1 _ |a Wlaschek, Meinhard
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700 1 _ |a Wagner, Matias
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700 1 _ |a Scharffetter-Kochanek, Karin
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700 1 _ |a Fischer-Posovszky, Pamela
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700 1 _ |a Read, Clarissa
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700 1 _ |a Crow, Yanick J
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700 1 _ |a Hirschenberger, Maximilian
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700 1 _ |a Sparrer, Konstantin M J
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773 _ _ |a 10.1038/s44319-025-00423-7
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