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@ARTICLE{Lang:278573,
      author       = {Lang, Johannes and Bergner, Tim and Zinngrebe, Julia and
                      Lepelley, Alice and Vill, Katharina and Leiz, Steffen and
                      Wlaschek, Meinhard and Wagner, Matias and
                      Scharffetter-Kochanek, Karin and Fischer-Posovszky, Pamela
                      and Read, Clarissa and Crow, Yanick J and Hirschenberger,
                      Maximilian and Sparrer, Konstantin M J},
      title        = {{D}istinct pathogenic mutations in {ARF}1 allow dissection
                      of its dual role in c{GAS}-{STING} signalling.},
      journal      = {EMBO reports},
      volume       = {26},
      number       = {9},
      issn         = {1469-221X},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DZNE-2025-00606},
      pages        = {2232 - 2261},
      year         = {2025},
      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.},
      keywords     = {Humans / Nucleotidyltransferases: metabolism /
                      Nucleotidyltransferases: genetics / ADP-Ribosylation Factor
                      1: genetics / ADP-Ribosylation Factor 1: metabolism / Signal
                      Transduction / Membrane Proteins: metabolism / Membrane
                      Proteins: genetics / Mutation / Fibroblasts: metabolism /
                      Interferon Type I: metabolism / Mitochondria: metabolism /
                      HEK293 Cells / ARF1 (Other) / Interferon (Other) /
                      Interferonopathy (Other) / STING (Other) / cGAS (Other) /
                      STING1 protein, human (NLM Chemicals) /
                      Nucleotidyltransferases (NLM Chemicals) / ADP-Ribosylation
                      Factor 1 (NLM Chemicals) / Membrane Proteins (NLM Chemicals)
                      / cGAS protein, human (NLM Chemicals) / ARF1 protein, human
                      (NLM Chemicals) / Interferon Type I (NLM Chemicals)},
      cin          = {AG Sparrer},
      ddc          = {570},
      cid          = {I:(DE-2719)1910003},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40128408},
      pmc          = {pmc:PMC7617634},
      doi          = {10.1038/s44319-025-00423-7},
      url          = {https://pub.dzne.de/record/278573},
}