{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lang J"],"funding":["Deutsche Forschungsgemeinschaft (DFG)","Bundesministerium für Bildung und Forschung","Agence Nationale de la Recherche (ANR)","Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg (MWK)","Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg","Deutsche Forschungsgemeinschaft","European Research Council","Agence Nationale de la Recherche","Medical Research Council","UKRI | Medical Research Council","Bundesministerium für Bildung und Forschung (BMBF)"],"pagination":["2232-2261"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7617634"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["26(9)"],"pubmed_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."],"journal":["EMBO reports"],"pubmed_title":["Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling."],"pmcid":["PMC7617634"],"funding_grant_id":["DFG; CRC1506; Project-ID 450627322 and CRC1149; Project-ID 251293561","IMMUNOMOD-01KI2014","786142","MC_UU_00035/11","CRC1279,SP 1600/9-1,SP1600/7-1","786142 E-T1IFNs","Margarete von Wrangell-Habilitationsprogramm","ANR 2022 - MITIgATe","520584003","ANR-10-IAHU-01,ANR-22-CE92-0012"],"pubmed_authors":["Lang J","Fischer-Posovszky P","Vill K","Crow YJ","Wagner M","Sparrer KMJ","Leiz S","Zinngrebe J","Hirschenberger M","Lepelley A","Scharffetter-Kochanek K","Read C","Wlaschek M","Bergner T"],"additional_accession":[]},"is_claimable":false,"name":"Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling.","description":"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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 May","modification":"2026-06-01T07:47:30.375Z","creation":"2026-04-08T10:32:11.013Z"},"accession":"S-EPMC7617634","cross_references":{"pubmed":["40128408"],"doi":["10.1038/s44319-025-00423-7"]}}