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000278573 1001_ $$aLang, Johannes$$b0
000278573 245__ $$aDistinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling.
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000278573 520__ $$aTight 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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000278573 650_7 $$2Other$$aARF1
000278573 650_7 $$2Other$$aInterferon
000278573 650_7 $$2Other$$aInterferonopathy
000278573 650_7 $$2Other$$aSTING
000278573 650_7 $$2Other$$acGAS
000278573 650_7 $$2NLM Chemicals$$aSTING1 protein, human
000278573 650_7 $$0EC 2.7.7.-$$2NLM Chemicals$$aNucleotidyltransferases
000278573 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$aADP-Ribosylation Factor 1
000278573 650_7 $$2NLM Chemicals$$aMembrane Proteins
000278573 650_7 $$0EC 2.7.7.-$$2NLM Chemicals$$acGAS protein, human
000278573 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$aARF1 protein, human
000278573 650_7 $$2NLM Chemicals$$aInterferon Type I
000278573 650_2 $$2MeSH$$aHumans
000278573 650_2 $$2MeSH$$aNucleotidyltransferases: metabolism
000278573 650_2 $$2MeSH$$aNucleotidyltransferases: genetics
000278573 650_2 $$2MeSH$$aADP-Ribosylation Factor 1: genetics
000278573 650_2 $$2MeSH$$aADP-Ribosylation Factor 1: metabolism
000278573 650_2 $$2MeSH$$aSignal Transduction
000278573 650_2 $$2MeSH$$aMembrane Proteins: metabolism
000278573 650_2 $$2MeSH$$aMembrane Proteins: genetics
000278573 650_2 $$2MeSH$$aMutation
000278573 650_2 $$2MeSH$$aFibroblasts: metabolism
000278573 650_2 $$2MeSH$$aInterferon Type I: metabolism
000278573 650_2 $$2MeSH$$aMitochondria: metabolism
000278573 650_2 $$2MeSH$$aHEK293 Cells
000278573 7001_ $$aBergner, Tim$$b1
000278573 7001_ $$aZinngrebe, Julia$$b2
000278573 7001_ $$00000-0001-8656-7291$$aLepelley, Alice$$b3
000278573 7001_ $$aVill, Katharina$$b4
000278573 7001_ $$aLeiz, Steffen$$b5
000278573 7001_ $$00000-0001-5821-1140$$aWlaschek, Meinhard$$b6
000278573 7001_ $$aWagner, Matias$$b7
000278573 7001_ $$00000-0002-9655-685X$$aScharffetter-Kochanek, Karin$$b8
000278573 7001_ $$aFischer-Posovszky, Pamela$$b9
000278573 7001_ $$00000-0002-4632-2684$$aRead, Clarissa$$b10
000278573 7001_ $$aCrow, Yanick J$$b11
000278573 7001_ $$0P:(DE-2719)9003503$$aHirschenberger, Maximilian$$b12$$udzne
000278573 7001_ $$0P:(DE-2719)9003481$$aSparrer, Konstantin M J$$b13$$eLast author
000278573 773__ $$0PERI:(DE-600)2025376-X$$a10.1038/s44319-025-00423-7$$gVol. 26, no. 9, p. 2232 - 2261$$n9$$p2232 - 2261$$tEMBO reports$$v26$$x1469-221X$$y2025
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